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Single Adult Stem Cell Can Self Renew, Repair Tissue Damage In Live Mammal
http://www.sciencedaily.com/releases/2008/12/081214190945.htm
The first demonstration that a single adult stem cell can self-renew in a mammal was reported at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.
The transplanted adult stem cell and its differentiated descendants restored lost function to mice with hind limb muscle tissue damage.
The adult stem cells used in the study, conducted at Stanford University, were isolated from a mixed population of satellite cells in the skeletal muscle of mice.
The skeletal adult muscle stem cells (MusSC), which live just under the membrane that surrounds muscle fibers, normally respond to tissue damage by giving rise to progenitor cells that become myoblasts, fusing into myofibers to repair the tissue damage.
The scientists transplanted the MusSC into special immune-suppressed "nude" mice whose muscle satellite cells had been wiped out in a hind limb by irradiation.
The mice would only be able to repair injury if the transplanted MuSC "took." The scientists, Alessandra Sacco and Helen Blau, had genetically engineered the transplanted MusSC to express Pax7 and luciferase proteins. As a result, every transplanted cell glowed under ultraviolet light and was easy to trace.
"To be able to detect the presence of the cells by bioluminescence was really a breakthrough," says Blau.
"It taught us so much more. We could see how the cells were responding, and really monitor their dynamics."
Through luminescent imaging as well as quantitative and kinetic analyses, Sacco and Blau tracked each transplanted stem cell as it rapidly proliferated and engrafted its progeny into the irradiated muscle tissue.
The scientists then injured the regenerated tissue, setting off massive waves of muscle cell growth and repair, and subsequently showed that the MuSC and descendents rescued the second animal's lost muscle healing function.
After isolating the luciferase-glowing muscle stem cells from the transplanted animal, the scientists duplicated, or cloned, the cells in the lab. Like the original MuSC, the cloned copies were intact and capable of self-renewal.
"We are thrilled with the results," says Sacco. "It's been known that these satellite cells are crucial for the regeneration of muscle tissue, but this is the first demonstration of self-renewal of a single cell."
The ability to isolate and then transplant skeletal adult muscle stems cells could have a wide impact in treating not only a variety of muscle wasting diseases such as muscular dystrophy but also severe muscle injuries or loss of function from aging and disuse.
In other experiments, the researchers transplanted between 10 and 500 luciferase-tagged MuSC into the leg muscles of mice.
These cells also proliferated and engrafted, forming new myofibers and fusing with injured fibers.
Unlike tumor cells, the transplanted stem cells achieved homeostasis, growing to a stable, constant level and ceasing replication.
After demonstrating that the transplanted stem cells proliferated and fully restored the animal's lost function, Sacco and Blau recovered new stem cells from the transplant with full stem cell potency, meeting the final "gold standard" test for adult multipotent stem cells.
The lead author presented, "Self-renewal and expansion of single transplanted muscle stem cells,"on Dec. 14, at Stem Cells I, Moscone Center.
Authors: A. Sacco, R. Doyonnas, P. Kraft, H.M. Blau, Microbiology and Immunology, Stanford University, Stanford, CA.
Newly discovered esophagus stem cells grow into transplantable tissue
http://www.therapeuticsdaily.com/news/article.cfm?contenttype=sentryarticle&contentvalue=1873999&channelID=28
Xinhua News Agency - Dec. 16, 2008
WASHINGTON, Dec 15, 2008 (Xinhua via COMTEX News Network) -- Researchers at University of Pennsylvania have discovered stem cells in the esophagus of mice that were able to grow into tissue-like structures and when placed into immune-deficient mice were able to form parts of an esophagus lining.
The investigators report their findings online on Monday in the Journal of Clinical Investigation.
"The immediate implication is that we'll have a better understanding of the role of these stem cells in normal biology, as well as in regenerative and cancer biology," says senior author Anil Rustgi. "Down the road, we might use these stem cells in replacement therapy for diseases like gastroesophogeal reflux disease (GERD) and also to understand Barrett's esophagus, a precursor to esophageal adenocarcinoma and how to reverse that before it becomes cancer."
The researchers set out to identify and characterize potential stem cells -- those with the ability to self renew -- in the esophagus to understand normal biology and how injured cells may one day be repaired.
First, they grew mouse esophageal cells they suspected were adult stem cells. Those cells formed colonies that self renewed. These cells then grew into esophageal lining tissue in a three- dimensional culture apparatus. "These tissue culture cells formed a mature epithelium sitting on top of the matrix," says Rustgi.
They then tested their pieces of esophageal lining in whole animals. When the tissue-engineered patches were transplanted under the skin of immune-deficient mice, the cells formed epithelial structures. Additionally, in a mouse model of injury of the esophagus in a normal mouse, which mimics what happens during acid reflux, green-stained stem cells migrated to the injured lining cells and co-labeled with the repaired cells, indicating involvement of the stem cells in tissue repair and regeneration.
Eventually the researchers will develop genetically engineered mouse models to be able to track molecular markers of esophageal stem cells. The group has already developed a library of human esophageal cell lines and is looking for human versions of markers already identified in mice.
"The ultimate goal is to identify esophageal stem cells in a patient, grow the patient's own stem cells, and inject them locally to replace diseased tissue with normal lining," says Rustgi.
In vitro derivation of functional insulin-producing cells from human embryonic stem cells
http://www.nature.com/cr/journal/v17/n4/full/cr200728a.html
Sorry, not enough time to fully edit, hilite this article
2nite...apologies.
Abstract
The capacity for self-renewal and differentiation of human embryonic stem (ES) cells makes them a potential source for generation of pancreatic beta cells for treating type I diabetes mellitus. Here, we report a newly developed and effective method, carried out in a serum-free system, which induced human ES cells to differentiate into insulin-producing cells. Activin A was used in the initial stage to induce definitive endoderm differentiation from human ES cells, as detected by the expression of the definitive endoderm markers Sox17 and Brachyury. Further, all-trans retinoic acid (RA) was used to promote pancreatic differentiation, as indicated by the expression of the early pancreatic transcription factors pdx1 and hlxb9. After maturation in DMEM/F12 serum-free medium with bFGF and nicotinamide, the differentiated cells expressed islet specific markers such as C-peptide, insulin, glucagon and glut2. The percentage of C-peptide-positive cells exceeded 15%. The secretion of insulin and C-peptide by these cells corresponded to the variations in glucose levels. When transplanted into renal capsules of Streptozotocin (STZ)-treated nude mice, these differentiated human ES cells survived and maintained the expression of beta cell marker genes, including C-peptide, pdx1, glucokinase, nkx6.1, IAPP, pax6 and Tcf1. Thirty percent of the transplanted nude mice exhibited apparent restoration of stable euglycemia; and the corrected phenotype was sustained for more than six weeks. Our new method provides a promising in vitro differentiation model for studying the mechanisms of human pancreas development and illustrates the potential of using human ES cells for the treatment of type I diabetes mellitus.
Keywords: human embryonic stem cell, direct differentiation, insulin-producing cell, diabetes
Top of pageIntroduction
Human pancreatic islet transplantation at present is the preferred therapeutic option for type I diabetes 1. However, this therapy is not widely utilized because of the severe shortage of donor islets 2. Human embryonic stem (ES) cells can be maintained in vitro for extended periods without loss of genetic stability, and are potential sources for generating a variety of specialized human cells needed for clinical applications. They hold the promise of serving as a source of insulin-producing donor cells in type I diabetes cell therapy 3, 4.
It has been reported that human ES cells can spontaneously differentiate into insulin-producing cells in vitro 5, 6. A five-stage protocol similar to that described by Lumelsky et al. 7 has been used to induce human ES cell differentiation into insulin-producing cells 8. However, further investigation is needed to confirm that human ES cells are indeed induced to become functional insulin-producing cells by these methods because of a possibility of exogenous insulin uptake 9 and the lack of functional demonstration by an in vivo transplantation assay. Recently, D' Amour et al. reported a stepwise protocol, by which they obtained pancreatic hormone-expressing endocrine cells, and the purified insulin-expressing cells had an insulin content approaching that of adult islets 10. However, the cells induced by their protocol released only a minimal amount of C-peptide in response to glucose stimuli. Furthermore, in vivo transplantation studies were not performed. Therefore, more effective approaches are required for inducing functional insulin-producing cells from human ES cells, which ideally should rescue the diabetic phenotype in vivo in an animal model.
In our previous study, we developed a novel three-stage induction method to induce mouse ES cells into insulin-producing cells, which could rescue diabetic mice after transplantation 11. Here, a modified approach in serum-free culture medium has been adopted to induce human ES cells to differentiate into functional insulin-producing cells by combining activin A, all-trans retinoic acid (RA) in chemically defined medium (CDM), and other maturation factors such as bFGF and nicotinamide in DMEM/F12. Using this method, which consisted of an incubation with activin A and RA in chemically defined medium (CDM) followed by maturation in DMEM/F12 serum-free medium supplemented with bFGF and nicotinamide, we showed that the human ES cell-derived cells expressed islet specific genes such as pdx1, insulin, C-peptide, glut2, glucagon, and amylase. The C-peptide-positive cells were TUNEL-negative and the percentage of C-peptide-positive cells achieved was more than 15%. The secretion of insulin by these cells was responsive to variations in glucose levels. After transplantation into diabetic nude mice, 30% of the animals showed an obvious rescue of their hyperglycemia phenotype, and this condition was maintained for more than six weeks.
Top of pageMaterials and Methods
Human ES cell culture and differentiation
The human ES cell lines H1 and H9 (from WiCell Research Institute, Inc.) were cultured in an undifferentiated state as described 3. We carried out all experiments in parallel with both cell lines. For differentiation, our protocol was designed as follows: in the first step, human ES cells were passaged onto 1% Matrigel (B&D Biosciences)-coated tissue culture dishes (Nunc). Then, the culture medium was changed to modified CDM: 50% IMDM (Gibco) plus 50% F12 NUT-MIX (Gibco), supplemented with Insulin-Transferrin-Selenium-A (1:100, Gibco) and 450 M monothioglycerol (Sigma), and 5 mg/ml albumin fraction V (Sigma) 12 or X-Vivo10 (Cambrex) supplemented with 55 M 2-Mercaptoethanol (Gibco) and 0.1% albumin fraction V (Sigma). Two days later, the cells were induced with CDM containing 50 ng/ml activin A (Sigma) for 4 d. After 4 d of activin A induction, the cells were transferred into CDM with 10-6 M RA (Sigma) for another 4 d. Then, the culture medium was changed from CDM to modified islet maturation medium 13: DMEM/F12 (Gibco), Insulin-Transferrin-Selenium-A (1:100, Gibco) and 2 mg/ml albumin fraction V (Sigma) with 10 ng/ml bFGF (Invitrogen) for the first 3 d and with 10 mM nicotinamide (Sigma) for the next 5 d. The cells were then digested by 0.5 mg/ml dispase (Gibco) and transferred into Ultra Low Attachment culture dishes (Costar) for 5 d to achieve islet maturation in suspension culture.
RT-PCR and Real-Time PCR analysis
Total RNA was extracted by TRIzol Reagent (Invitrogen) from the cells during the induction process and from kidneys of transplanted mice. RNA was then reverse-transcribed into cDNA by MMLV reverse transcriptase (Promega).
PCR was performed with Ex Taq polymerase (TaKaRa) following the manufacturer's protocol. The cycle conditions were as follows: 94 °C for 5 min followed by 35 cycles (94 °C denaturation for 50 S, 56-58 °C annealing for 30 S, 72 °C elongation for 40 S), with a final incubation at 72 °C for 4 min. The primers are shown in the supplemental information, Table S1.
Real-time PCR analysis was performed on ABI PRISM 7300 Sequence Detection System using the SYBR Green PCR Master Mix (TOYOBO). The PCR reaction consisted of 12.5 l of SYBR Green PCR Master Mix, 1 l of 10 M forward and reverse primers, 10.5 l of water, and 1 l of template cDNA in a total volume of 25 l. Cycling was performed using the default conditions of the ABI 7300 SDS Software 1.3.1: 95 °C 2 min, followed by 35 cycles of 95 °C for 15 s and 60 °C for 1 min. The relative expression of each gene was normalized against gapd. The primers of assayed genes, including -actin, glucokinase, nkx6.1, IAPP, pax6 and Tcf1, were designed specifically for human genes. The primer sequences are shown in the supplemental information, Table S2.
Immunohistochemistry assay
Induced cells were fixed in 4% paraformaldehyde and washed three times by PBS, then incubated with PBS containing 0.3% TritonX-100 (Sigma) and 10% normal serum for 40 min at room temperature. Especially for nuclear antigens, the concentration of TritonX-100 was adapted to 0.5% and incubation time to 1 hour. The cells were then incubated with the primary antibody: Goat anti-human Sox17 antibody (1:100, R&D SYSTEMS), Mouse anti-human insulin monoclonal antibody (1:100, CHEMICON), Rabbit anti-human C-peptide antibody (1:200, Linco), glucagon antibody (Rabbit polyclonal IgG, 1:200, Santa Cruz), pdx1 antibody (Rabbit or Goat polyclonal IgG, 1:200, from Dr. C Wright), amylase antibody (Rabbit polyclonal IgG, 1:500, Sigma), ngn3 antibody (Goat polyclonal IgG, 1:200, Santa Cruz) or somatostatin antibody (Rabbit polyclonal IgG, 1:200, Santa Cruz), overnight at 4 °C, and further incubated with the respective secondary antibody: TRITC-conjugated goat anti-rabbit IgG, FITC-conjugated rabbit anti-goat IgG, FITC-conjugated Goat anti-Mouse IgG (1:200, Santa Cruz), FITC-conjugated Donkey anti-goat IgG or TRITC-conjugated Donkey anti-rabbit IgG (1:200, Jackson ImmunoResearch, INC.). In all immunochemistry assays negative staining controls were carried out by omitting the primary antibody. Nuclei were detected by DAPI (Sigma) staining. Images were captured using Olympus microscope IX-71, LEICA microscope DM4000B or LEICA confocal microscope TCS-SP2.
The percentage of Sox17-, pdx1- and C-peptide-positive cells were calculated using Image-Pro Plus software (Media Cybernetics) as follows: an area to be measured was outlined by a tracer, with the number of counting frames preset so that the scope sampled the measuring sites randomly. The software counted the value of the respective chosen area. We utilized DAPI staining to estimate the amount of total cells. For counting the percentage of pdx1- or C-peptide-positive cells, the positive areas were estimated by the software in the same way. The percentage was calculated by the following formula: C-peptide (or pdx1) positive area/whole DAPI positive area. Pictures were taken from at least three independent cultures and fifty random different scopes of the differentiated cells to estimate the positive cell percentage.
The DeadEnd™ Fluorimetric TUNEL System (Promega) was utilized to perform the cell apoptosis assay. Images were captured using LEICA confocal microscope TCS-SP2.
ELISA assay
To test whether the insulin release of differentiated cells was glucose-dependent, two glucose concentrations (2.5 mM and 27.5 mM) were used. After pre-incubation with Krebs-Ringer buffer at 37°C for 90 min, the cells were incubated with Krebs-Ringer buffer containing 2.5 mM glucose at 37 °C for 15 min. To induce insulin release, the cells were incubated with 27.5 mM glucose for another 15 min. Then the respective conditioned media were collected and tested for the content of released insulin with a Rat/Mouse Insulin ELISA Kit (Linco). To determine the C-peptide content in the differentiated cells, we treated the cells with lysis buffer: 50 mM Tris-Cl (pH 7.5), 150 mM NaCl, 2 mM EDTA and 1% SDS. The C-peptide concentration in the cells was determined by using a Human C-peptide ELISA Kit (Linco) and the total intracellular protein content was detected with a BCATM Protein Assay Kit (PIERCE).
Transplantation
The Institutional Animal Care and Use Committees of Peking University approved all animal procedures. Prior to transplatation, Streptozotocin (STZ, Sigma) was injected i. p. at 40 mg/kg/day into 4-6 week-old BALB/c male nude mice for 5 d to induce experimental diabetes. Blood glucose was measured by GlucoTREND2 (Roche) from snipped tail. Only mice with blood glucose levels stably above 13.9 mM after the STZ injections were used in these transplantation experiments. For transplantation, about 1106 differentiated cells in the final induction stage were injected into the left renal capsule. PBS or cells without activin A and RA induction were used as control. A glucose tolerance test was performed by i.p. injection of glucose (2.5 g/kg body weight) after overnight fasting. After more than six weeks, the cell-transplanted kidneys were removed from those mice whose hyperglucemia was rescued after induced cell transplantation. Cryostat sections of the operated kidneys were prepared and C-peptide or pdx1 expression of the transplanted cells in the renal capsule was confirmed by immunohistochemistry. The human ES-derived cells were detected by mouse anti-human nuclei monoclonal antibody (1:30, CHEMICON). Images were captured using an LEICA microscope DM4000B.
Top of pageResults
Derive insulin-positive cells from human ES cells by the combination of activin A, RA and maturation factors
Here we developed an effective method with activin A, RA and other maturation factors in serum-free medium to induce human ES cells to differentiate into functional insulin-producing cells. This induction process is illustrated in Figure 1. We first determined whether activin A could induce definitive endoderm formation from human ES cells. Undifferentiated H1 cells were passaged onto 1% Matrigel-coated dishes and cultured for 4 d in CDM system containing activin A. Results from our previous study 11, as well as the work of others 18, 19, 20, showed that high concentrations of activin A can lead to efficient endoderm differentiation. We tested with various concentrations of activin A, and found that activin A at a concentration as low as 50 ng/ml was sufficient to induce human ES cells into endoderm lineages (data not shown). RT-PCR analyses revealed that activin A treatment at 50 ng/ml resulted in an increased expression of endoderm genes such as sox17 and hnf4 (Figure 2B). Importantly, immunostaining further demonstrated that activin A caused a significant increase in the number of cells expressing Brachyury, a mesendoderm marker; and Sox17, an endoderm marker 14. We also observed a decrease in the number of AFP-positive cells compared to a control experiment without activin A-induction (Figure 2A). Control staining of the differentiated human ES cells after activin A induction, omitting the primary antibody, was negative (data not shown).
Figure 1.The sketch of human ES cell differentiation protocol. Undifferentiated human ES cells were first cultured in CDM for 2 d then transferred into CDM containing activin A for 4 d. Then, the differentiated cells were further induced with RA in CDM for 4 dand transferred from CDM culture medium into DMEM/F12 islet maturation medium with bFGF added as a pancreatic cell maturation factor for 3 d. Finally, the differentiated cells were switched to DMEM/F12 islet maturation medium containing bFGF and nicotinamide for another five days and transferred onto a hydrophobic plate in the same medium for a five-day suspension culture.
Full figure and legend (46K)
Figure 2.Activin A induced definitive endoderm differentiation from human ES cells. (A) After cultured in CDM with activin A for 4 d, a number of cells expressing Brachyury and Sox17 but not AFP appeared. However, without activin A induction, few Brachyury-positive cells and many Sox17 and AFP double positive cells were detected (bar 20 m). (B) Activin A treatment resulted in an increased expression of endoderm genes such as sox17 and hnf4.
Full figure and legend (223K)
Then, pancreatic lineage differentiation from human ES cells was further induced with 10-6M RA in CDM for another 4 d. 10-6M RA was found to be sufficient for pancreatic progenitor differentiation from human ES cells, and higher concentration of RA could induce cell apoptosis (data not shown). At this stage, some cells formed clusters (Figure 3B). Immunofluorescence analysis revealed that in these differentiated cells, there were pdx1 positive cells, which were not co-stained with the amylase-positive cells. In some cells, the expression of ngn3 and the faint expression of C-peptide could be detected (Figure 3C). From three independent cultures, the percentage of pdx1 positive cells was on average 25%. Control staining of the differentiated human ES cells after activin A and RA induction was performed as shown in Figure 3C. After both activin A and RA induction, the mRNA levels of pdx1, hnf4 and hlxb9, three transcription factors critical for early pancreas development, were shown by RT-PCR to have been induced (Figure 3D). In a control experiment without activin A and RA treatment, spontaneously differentiated human ES cells did not express pdx1, hnf4 or hlxb9. The presence of activin A alone induced only weak expression of the pdx1 and hnf4 genes, while RA by itself induced only hlxb9 expression. These results indicate that in the CDM culturing system, the sequential treatment of human ES cells with activin A and RA leads to more efficient differentiation into pancreatic cells.
Figure 3.Pancreatic lineage differentiation from human ES cells was further induced with RA. (A) human ES cells cultured in CDM without activin A and RA treatment (bar 100 m). (B) Small clusters formed from differentiated human ES cells in CDM with activin A and RA treatment (bar 100 m). (C) pdx1 and Amylase staining, ngn3 and C-peptide staining of differentiated human ES cells in CDM after activin A and RA induction. Negative control staining of the differentiated human ES cells was shown in the lower panel (bar 40 m). (D) With both activin A- and RA-induction, the mRNA levels of pdx1, hnf4 and hlxb9 were induced as shown by RT-PCR detection. Without activin A and RA treatment, spontaneously differentiated human ES cells did not express pdx1, hnf4 or hlxb9. The presence of activin A alone induced only weak expression of pdx1 and hnf4 genes and RA alone induced only hlxb9 expression.
Full figure and legend (204K)
Following the treatment with activin A and RA, we transferred the differentiated cells from CDM to the DMEM/F12 islet maturation medium containing bFGF 15 as a pancreatic cell maturation factor for three days (Figure 4A). Finally, the differentiated cells were switched to DMEM/F12 islet maturation medium containing nicotinamide 16 and bFGF for another three days and then transferred onto a hydrophobic plate in the same medium for a five-day suspension culture. In this final stage, many differentiated cells formed spherical clusters (Figure 4B) and expressed pancreatic cell markers such as pdx1, insulin, glucokinase and glut2, as determined by RT-PCR analysis (Figure 4C). To detect whether these clusters expressed pancreatic specific markers such as C-peptide, glucagon and amylase, we plated the cells in suspension culture onto 1% Matrigel coated dishes to allow the aggregated clusters to adhere to a solid surface. These cells were then used for immunofluorescence analysis by confocal microscopy. As shown in Figure 5, among the differentiated cells, there were islet-like cluster structures and most of the cells in the clusters co-expressed C-peptide and pdx1, indicating that these cells were mature insulin-producing cells. In addition, immunostaining showed that within or around the pdx1 positive clusters, there were some pdx1 negative cells expressing pancreatic endocrine hormones such as glucagon or somatostatin. Some amylase positive cells were found near the pdx1 positive clusters, which suggested that pancreatic exocrine cells also existed in the differentiated cells after final induction. In the final stage, there were also pdx1 positive and C-peptide negative cells. However, these cells were mostly in a monolayer and not in clustered structures, which could be still in the pancreatic progenitor stage (data not shown). In the islet-like clusters, there were a few pdx1 and somatostatin co-expressing cells; however, we did not find any expamples of cells that co-expressed pdx1 with either glucagon or amylase (Figure 5). To confirm whether there were any remaining completely undifferentiated cells, we checked the Oct4 expression by immunohistochemistry and found no Oct4-positive cells in the final induction stage (data not shown). Negative control staining of the differentiated human ES cells after the final stage of induction was also performed (data not shown).
Figure 4.The cell morphology of the differentiated human ES cells at the final induction stage. The differentiated human ES cells expressed islet genes as detected by RT-PCR. (A) After activin A and RA induction, human ES cells were transferred into DMEM/F12 islet maturation medium with bFGF and cultured in an adhesion plate for 3 d. (B) Differentiated cells were transferred onto a hydrophobic plate for suspension culture and cultured for 3 d (bar 100 m). (C) The differentiated human ES cells after the final induction step expressed islet genes, as detected by RT-PCR (upper panel); human ES cells differentiated without treatment by our induction method were used as control (lower panel).
Full figure and legend (180K)
Figure 5.Immunostaining indicated that the terminally differentiated cells expressed pancreatic endocrine markers including Pdx1, C-peptide, Glucagon and Somatostatin and the exocrine marker Amylase (bar 50 m).
Full figure and legend (350K)
As shown in Figure 6A, data collected from three independent cultures indicated that the percentage of C-peptide-positive cells were more than 15% (16.9 4%) using our induction method. To exclude the possibility that apoptotic cells might take up insulin from the medium 10, we analyzed whether the insulin-producing cells were apoptotic using a TUNEL assay. We found no C-peptide-positive cells co-stained with TUNEL thus indicating that the C-peptide-positive cells were not apoptotic (Figure 6B and 6C). Similar results were found in the differentiated cells derived from the H9 human ES cell line (data not shown).
Figure 6.The C-peptide-positive cells in the final induction stage were TUNEL-negative and the percentage of C-peptide-positive cells exceeded 15%. The secretion of insulin by the terminally differentiated cells was responsive to the glucose level. The intracellular C-peptide content of the differentiated cells was measured. (A) The statistics of C-peptide-positive cells within the differentiated cells in the final induction stage. (B) As a positive control, differentiated human ES cells were treated with DNase to induce apoptosis and stained with TUNEL. Data merged with DAPI (bar 40 m). (C) There were no C-peptide-positive cells that co-stained with TUNEL, which indicated that the C-peptide-positive cells were not apoptotic (bar 40 m). And the C-peptide showed clear cytoplasmic staining. (D) The secretion of insulin by the cells differentiated in suspension culture was responsive to the glucose level. However, insulin secretion from the cells in adhesion culture did not respond to glucose stimulation. (E) The intracellular C-peptide content of differentiated human ES cells was responsive to glucose content. *Data were analysed using a standard t-test where P<0.05 was considered to be significant. Insulin secretion (and C-peptide content) was compared between conditions where the cells were stimulated with either a low glucose concentration or a high glucose concentration.
Full figure and legend (193K)
Insulin secretion by the induced cells responded to glucose stimulation
To analyze whether the insulin secretion from these human ES cells derived insulin-producing cells was regulated by glucose, we treated the induced cells with Krebs-Ringer buffer containing low (2.5 mM) or high (27.5 mM) glucose concentrations, and then examined the insulin release in Krebs buffer by ELISA. We found that for the cells induced in the suspension culture, the insulin secretion was increased by 100% in the high glucose medium comparing to the low glucose medium (Figure 6D). We then lysed the differentiated cells and checked their intracellular C-peptide content. As shown in Figure 6E, the intracellular C-peptide content in suspension culture was also increased by 100% in the high glucose medium compared to the low glucose medium (Figure 6E). The intracellular C-peptide content in suspension culture was more than 0.35 ng/mg, which further suggested that the insulin produced by these cells was not taken up from the culture medium. Comparing between suspension cultures and adhesion cultures (Figure 6E), it is apparent that the suspension culture resulted in more efficient insulin production in the differentiated cells using our approach.
Transplantation of induced cell rescues hyperglycemia in thirty percent of the diabetic nude mice
To investigate whether the induced cells could function in vivo, we transplanted the differentiated cells under the renal capsules of diabetic nude mice. The blood glucose of 30% of the induced cell-transplanted mice (n=6) was maintained at normal levels (<13.9 mM) for nearly six weeks and the other 70% cell-transplanted mice (n=13) maintained hyperglycemia. In the control groups, consisting of non-induced cell-transplanted (n=12) and PBS-transplanted (n=11) mice, no mouse exhibited restoration of stable euglycemia. More than six weeks after transplantation, we removed the cell-transplanted kidney from the blood glucose rescued nude mice, and they regained hyperglycemia within three days after the operation and maintained it for at least two weeks (Figure 7A). The glucose tolerance test indicated that these 30% of nude mice with rescued blood glucose levels also attained improved glucose regulation capability compared to that of control-operated mice (Figure 7B).
Figure 7.Transplantation of the induced human ES cells partially ameliorates diabetic symptoms. cell markers were detected in the kidney capsules transplanted with the cells induced by our approach. (A) The blood glucose test and (B) intraperitoneal glucose tolerance test of the operated mice transplanted with the induced cell, non-induced cell and PBS. (a, The 30% rescued diabetic nude mice, which were transplanted with induced human ES cells (n=6). b, The other 70% induced cell-transplanted mice (n=13) that remained hyperglycemic. c, The diabetic nude mice which were transplanted with the human ES cells without activinA and RA induction as control (n=12). d, The diabetic nude mice which were only injected with PBS (n=11)). * Data were analysed using a standard t-test where P<0.05 was considered to be significant. The blood glucose (and glucose tolerance) of 30% of the induced cell-transplanted diabetic nude mice with the phenotypic rescue was compared to mice injected with PBS or transplanted with non-induced cells. (C) When the induced cells were transplanted into diabetic nude mice, C-peptide-positive and pdx1-positive cells derived from human ES cells were detected after six weeks. The C-peptide- or pdx1-positive cells were co-stained by a human nuclei-specific antibody (bar=50 m). (D) When the differentiated hES cells without activin A and RA induction were transplanted, almost no C-peptide positive cells were detected after one month (bar=50 m). (E) Human specific -actin and beta cell markers were detected in the grafted left kidney. The results were normalized against the expression in the right kidney that did not receive cell transplantation.
Full figure and legend (322K)
To confirm that the human ES cell-derived beta cells could function in vivo, we first assayed for the presence of human ES cell-derived C-peptide or pdx1 positive cells in the graft kidney. We observed that the C-peptide-positive cells and pdx1-positive cells were both co-stained by a human nuclei-specific antibody thus indicating that these C-peptide- or pdx1-positive cells were derived from the injected human ES cells (Figure 7C). We also detected the expression of glut2 and PC1/3, two important functional markers, in the graft kidney by immunochemistry assay (Supplementary information, Figure S1). The C-peptide positive cells could also be detected in the renal capsules of the other 70% cell-transplanted mice that remained hyperglycemic, but at much fewer numbers than that in mice with rescued blood glucose levels (data not shown). When the differentiated hES cells without exposure to activin A and RA were transplanted, no C-peptide positive cells were detected after one month (Figure 7D). Moreover, we designed several human specific primers to further confirm the expression of human beta cell marker genes, including glucokinase, nkx6.1, IAPP, pax6 and Tcf1. Compared with the right kidney that did not receive cell transplantation, human specific -actin and the beta cell marker genes were only expressed in the grafted left kidney, and their expressions were maintained even after more than two months post-transplantation (Figure 7E). These results showed that the human ES cell-derived insulin-producing cells were functional in vivo. Moreover, no Oct4-expressing cells were detected in the grafts (data not shown). And we followed these mice for three months post-transplantation and did not observe any teratoma formation.
We next assayed for blood C-peptide level in all of the recipients. Initially, we were unable to detect human C-peptide in mouse serum at both the fast and fed state. However, thirty minutes after glucose i.p. injection, we detected human C-peptide in serum but only in induced cell-transplanted mice (0.5 ng/ml, n=5). Although the level of human C-peptide detected in serum was quite low, these data showed that the induced cells generated by our protocol were functional in vivo.
Top of pageDiscussion
In this study, we have successfully developed a new approach for directing human ES cell differentiation into functional insulin producing cells within 20 d. This newly developed method is based on our previous study, which had demonstrated that the combination of activin A and RA efficiently induces insulin-producing cells from mouse ES cells 11. However, the previously established method for mouse ES cell differentiation is not directly applicable for human ES cells (data not shown). Several major improvements have been devised to establish an effective approach on human ES cells.
First, the entire induction process was performed in serum-free medium including the first two stages and a DMEM/F12 islet maturation medium in the third stage. Initially, we failed to obtain definitive endoderm cells from human ES cells by using activin A in 10% serum containing medium (data not shown). However, as we changed the induction process with the serum-free medium, the definitive endoderm marker Sox17 14 was detectable as shown in Figure 2B, which indicated that activin A was effective in inducing definitive endoderm differentiation from human ES cells. The serum-free culturing medium avoided the negative effects of unknown factors in the serum on human ES cell differentiation, and also made it possible to more effectively study the precise effects of different growth factors or signaling pathways on human ES cell differentiation.
Second, using our approach, we found that a suspension culture was apparently better for beta cell maturation than an adherent culture based on our insulin secretion and intracellular C-peptide content test. Interestingly, a similar effect has been observed in human islet cell culture in vitro. Lechner A et al reported that culturing of human islet cells in a monolayer leads to the loss of insulin expression and that re-aggregation of the expanded islet cells was subsequently required to increase insulin expression in vitro 17.
Our previous study 11 and the results presented here show that the combination of activin A and RA can effectively induce both mouse and human ES cells to differentiate into insulin-producing cells. The individual effect of activin A and RA on endoderm and pancreas development has also been demonstrated by several other groups 18, 19, 20, 21, 22, 23, 24. It has been shown that mouse and human ES cells can be efficiently induced into Sox17-positive definitive endoderm by activin A treatment 18, 19, 20. RA has been reported to be critical for early pancreas formation during zebrafish and mouse embryonic development 21, 22, 23, 24. In our study, as shown in Figure 3, when induced by activin A alone, human ES cells weakly express the pancreatic early transcription factors pdx1 and hnf4a. With RA induction alone, human ES cells express only hlxb9. However, when human ES cells were induced with a combination of activin A and RA in sequence, the expression of hlxb9, pdx1 and hnf4a were all increased significantly. These results suggest that the combination of activin A and RA is an effective method to promote pancreas specification from human ES cells, which mimics the in vivo pancreatic development pathway, i.e. from blastocyst to endoderm and then from endoderm to pancreas specification.
When human ES cells induced by our stepwise approach were transplanted into STZ-treated diabetic nude mice, beta cell markers including C-peptide, pdx1, glut2, PC1/3, glucokinase, nkx6.1, IAPP, pax6 and Tcf1 were detected in kidney capsules six weeks later, indicating that the insulin-producing cells could successfully survive in vivo. We further showed that via injection into diabetic nude mice the induced human ES cells could rescue the hyperglycemia phenotype. The blood glucose levels of all the operated mice showed an obvious decrease in the first week compared to the control, and 30% of the operated mice subsequently exhibited stable euglycemia for more than six weeks. This 30% rescue rate might be due to two reasons. First, the procedure involved xenotransplantation such that human cells were injected into the renal capsules of nude mice. The physiological differences between human and mice could very likely impair the function of transplanted human ES cell-derived islet-like cells. Second, even for the model involving the transplantation of human islet into nude mice, islet purity and insulin content are both critical for proper graft function [28]. The presence of exocrine tissue in islet preparations has been previously shown to impair islet engraftment in nude mice 26. Impure islets have been shown to induce tissue necrosis and subsequent fibrosis at the implant site, consequently delaying the revascularization process 27. In the approach described here, there are still pancreatic exocrine cells within the induced islet-like clusters that might affect the function of the transplanted cells. Therefore, further work is needed to purify the pancreatic beta cells from the induced human ES cells so as to improve the differentiation efficiency for successful transplantation.
Our present protocol was designed to mimic pancreatic islet development and included three developmental events: definitive endoderm formation, pancreas specification and endocrinal islet maturation. Our data suggests that strategies which aim to mimic in vivo organogenesis should be a promising approach for differentiating ES cells into pancreatic islet cells. D' Amour et al. also reported a complicated stepwise protocol 10, from which they obtained pancreatic endocrine hormone-expressing cells. In their studies, insulin-expressing cells were selected by using the zinc-chelating dye dithizone. These purified dithizone-stained cells had an insulin content approaching that of adult islets. However, C-peptide release from the cells induced by their protocol did not respond well to glucose stimulation. Furthermore, many immature cells that co-expressed insulin and glucagon were also present. Moreover, in vivo functional transplantation studies were not performed. In our present work, the secretion of insulin and the production of C-peptide from the cells induced by our protocol corresponded to the variations in glucose levels used in our studies. Also, no pdx1 and glucagon co-expressing cells were observed. Transplantation of these induced cells into diabetic mice was able to partially rescue the recipients, and the expression of several beta cell marker genes could be observed in the graft even after more than two months post-transplantation. The rate of C-peptide-positive cells was approximately 15% and the rescue efficiency was approximately 30%, suggesting that further improvement is needed.
In summary, an effective stepwise approach utilizing the combination of activin A, RA and other maturation factors has been shown to induce human ES cells to differentiate into functional insulin-producing cells, and these differentiated cells are able to rescue diabetic nude mice to a certain extent after transplantation. This approach offers a promising in vitro model for studying human pancreas development and also helps fulfill the urgent need of an ample supply of insulin-producing cells for cell transplantation therapy in type I diabetes.
Wei Jiang1,*, Yan Shi1,5,*, Dongxin Zhao1, Song Chen1, Jun Yong1, Jing Zhang2, Tingting Qing1, Xiaoning Sun1,3, Peng Zhang1, Mingxiao Ding1, Dongsheng Li4 and Hongkui Deng1,2,3
1Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, China
2Beijing Laboratory Animals Research Center, Beijing 100012, China
3Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, the University Town, Shenzhen 518055, China
4Provincial Key Laboratory of Embryonic Stem Cell Research, Tai-He Hospital Yunyang Medical College, 32 S. Renmin Rd., Shiyan 442000, China
Correspondence: Hongkui Deng, Tel: 86-10-6275-6954; Fax: 86-10-6275-6954 E-mail: hongkui_deng@pku.edu.cn; Dongsheng Li, Tel: 86-719-8801418; Fax: 86-719-8801418 E-mail: dsli@yymc.edu.cn
*These two authors contributed equally to this work.
5Present address: The Scripps Research Institute, Chemistry Department, SP3130, 10550 North Torrey Pines Road, La Jolla, CA, USA.
Received 12 March 2007; Revised 13 March 2007; Accepted 13 March 2007.
Transplanted Fat Cells Restore Function After Spinal Cord Injury
http://www.sciencedaily.com/releases/2008/12/081210122254.htm
(Dec. 10, 2008) — A new study suggests that mature adipocytes - fat cells - could become a source for cell replacement therapy to treat central nervous system disorders.
According to the study's lead researcher, Dr. Yuki Ohta of the Institute of Medical Science, St. Mariana University School of Medicine, Kawasaki, Japan, adipose-derived stem/stromal cells have in the past been shown to differentiate into neuronal cells in an in vitro setting. In their study, for the first time fat cells have been shown to successfully differentiate into neuronal cells in in vivo tests. The fat cells are grown under culture conditions that result in them becoming de-differentiated fat (DFAT) cells.
"These cells, called DFAT cells, are plentiful and can be easily obtained from adipose tissue without discomfort and represent autologous (same patient) tissue," said Ohta. "DFAT cells, with none of the features of adipocytes, do have the potential to differentiate into endothelial, neuronal or glial lineages."
The research team reported that DFAT cells expressed neurotrophic factors, such as BDNF and GDNF, prior to and after transplantation and which likely contributed to the promotion of functional recovery.
According to Ohta and colleagues, tests in animal models confirmed that the injected cells survived without the aid of immunosuppression drugs and that the DFAT-grafted animals showed significantly better motor function than controls.
"We concluded that DFAT-derived neurotrophic factors contributed to promotion of functional recovery after spinal cord injury (SCI)," said Ohta. "Transplanting DFAT cells into SCI rats significantly promoted the recovery of their hind limb function."
"These studies demonstrate the ability to obtain stem cells from a patient's own fat that can help repair injury to the spinal cord," said Paul R. Sanberg, PhD, DSc, at the University of South Florida Health, and Coeditor-in-chief of Cell Transplantation.
This study was published Cell Transplantation (Vol.17, No. 8.)
First Functional Stem-cell Niche Model Created
http://www.sciencedaily.com/releases/2008/12/081210131036.htm
(Dec. 10, 2008) — Like it or not, your living room probably says a lot about you. Given a few uninterrupted moments to poke around, a stranger could probably get a pretty good idea of your likes and dislikes, and maybe even your future plans. Scientists at the Stanford University School of Medicine employing a similar "peeping Tom" tactic to learn more about how stem cells develop have taken a significant step forward by devising a way to recreate the cells' lair — a microenvironment called a niche — in an adult animal.
"We have isolated the cells in mouse bone that make bone and cartilage from scratch and attract wandering blood stem cells," said Irving Weissman, MD, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and the director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The stem cells can and do settle in these 'niches' and make blood that is exported to the body."
The research marks the first time that scientists have successfully recreated a functional stem-cell niche for further study. Weissman and his colleagues plan to use the model system to determine how the niche environment interacts with the blood stem cells to affect their development and fate, and how leukemias respond to these niches. They will also investigate the bone and cartilage healing capacity of these cells.
Weissman is the senior author of the study, which will be published Dec.10 in the advance online issue of Nature. Graduate student Charles Chan shares first authorship with postdoctoral scholars Ching-Cheng Chen, PhD, and Cynthia Luppen, PhD.
Blood-forming stem cells typically reside in the bone marrow. The researchers found that a specific subset of fetal mouse bone cells could not only take up residence and produce bone when injected near the kidney of an adult animal, but they also generated a bone marrow cavity that sheltered host-derived blood stem cells. In contrast, other subsets of fetal bone cells generated only bone.
"An amazing part of this study was the formation of organized bone, cartilage and blood stem cell niches from an initially dispersed set of cells," said Weissman, who is also a member of the Stanford Cancer Center. "If we can find the daughter cell in this population that is responsible for niche formation, we may learn enough to eventually be able to expand blood stem cell numbers so that a small number, say from umbilical cord blood, can be made into enough to treat several patients with failure of blood formation."
Suppressing the expression of factors involved in a specialized bone-building process called endochondrial ossification in the host mouse stopped the formation of the marrow cavity and the recruitment of host stem cells. Using similar fetal bone cells from parts of the skeleton that do not undergo the process — such as the skull and the jaw — also blocks cavity formation. The findings suggest that endochondrial ossification is a necessary step in setting up house for stem cells.
Other Stanford scientists involved in the research include postdoctoral scholar Jae-Beom Kim, PhD; associate professor of surgery Jill Helms, DDS, PhD; associate professor of medicine Calvin Kuo, MD, PhD; and senior postdoctoral fellow, Daniel Kraft, MD.
The research was funded by the National Institutes of Health and by Hope Street Kids.
Scientists Prove Endothelial Cells Give Rise To Blood Stem Cells
http://www.sciencedaily.com/releases/2008/12/081203131039.htm
(Dec. 6, 2008) — Stem cell researchers at UCLA have proven definitively that blood stem cells are made during mid-gestational embryonic development by endothelial cells, the cells that line the inside of blood vessels.
While the anatomic location in the embryo where blood stem cells originate has been well documented, the cell type from which they spring was less understood. The UCLA finding, published in the Dec. 4, 2008 issue of the journal Cell Stem Cell, puts to rest a long-standing controversy over whether blood stem cells were created, or born, in the endothelium or originated from another cell type in a nearby location.
Researchers from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA used a cell fate tracing technique to identify the source of blood stem cells. They genetically marked endothelial cells to discover what other cells they gave rise to and where those cells migrated to in the body.
"We genetically traced the endothelial cells to find out what they became over time," said Luisa Iruela-Arispe, senior author of the paper, a professor of molecular, cell and developmental biology and director of the Cancer Cell Biology Program Area at UCLA's Jonsson Comprehensive Cancer Center.
"In that way, we were able to understand that, within the embryo, endothelial cells were responsible for the generation of blood stem cells. They make blood, they aren't just the pipes that carry it."
The finding ultimately could lead to new therapies for certain blood disorders and cancers, said Ann Zovein, the first author of the study and a California Institute for Regenerative Medicine-Broad Stem Cell Research Center Training Grant postdoctoral fellow in Iruela-Arispe's lab.
Blood stem cells currently cannot be grown outside of the body without losing their "stemness," meaning they then differentiate into the different cells that make up blood, including red blood cells, white blood cells and platelets. If blood stem cells can be gown outside the body from endothelial cells and only self-renew, or make more of their own kind, researchers may one day be able to reprogram blood vessel cells to produce blood stem cells to replace the bone marrow in transplants or the mutated blood cells that result in diseases like leukemia.
"We found that endothelial cells are capable of making blood stem cells within embryonic areas that prevent differentiation into other lineages," Zovein said. "In trying to understand how blood stem cells arise from the endothelium, we may learn enough to be able to grow pure, designer blood stem cells outside the human body."
For example, researchers may some day be able to take a blood vessel from a patient and grow blood stem cells specific to that patient, which could be used for bone marrow transplantation. Since the blood stem cells originated from the patient, there would be no need to find a matching donor to provide the marrow. The cells also could be used to replace diseased cells that result in cancer, providing a new way to treat malignancies such as leukemia.
The creation of blood stem cells by endothelial cells occurs at a specific time in embryonic development and researchers want to know what takes place biologically during that period, what specific cell signaling pathways are sending the messages to make blood stem cells. Iruela-Arispe and her team hope to mimic the embryonic environment in the lab to create blood cells that don't differentiate.
"Next we need to understand what signaling mechanisms are at work that allow endothelial cells to make blood stem cells," Iruela-Arispe said. "We need to find out how we can program the endothelial cells to make blood stem cells, what's important in the embryonic blood vessel wall that allows for this phenomenon and whether we can reprogram adult blood vessels to do the same thing."
While this study was done in mouse models, Iruela-Arispe and her team will be working with human endothelial cells to confirm their work and further uncover the cell signaling mechanisms in play.
Stem cells: A new pathway for stem cell ageing and renewal
http://www.signaling-gateway.org/update/updates/200812/nrc2547.html
The transcriptional regulator high-mobility group A2 (HMGA2) promotes neural stem cell self-renewal by negatively regulating INK4A and ARF expression.
Stem cells have the potential for self-renewal and are therefore able to persist throughout life in a diverse range of tissues. However, their self-renewing capacity declines with age. What mechanisms are responsible for the differences between young and ageing stem cells? The discovery of a novel pathway involving high-mobility group A2 (HMGA2), INK4A and ARF has recently provided exciting new insights.
Both INK4A and ARF expression increase in ageing tissues, suggesting that a pathway involving these tumour suppressor genes may mediate the differences in self-renewal between old and young stem cells. Sean Morrison and colleagues have now shown that HMGA2, a transcriptional regulator, reduces INK4A and ARF expression in young mice, thus promoting neural stem cell self-renewal. Hmga2 was identified in a full-genome analysis that was carried out by the authors to search for genes that were preferentially expressed in stem cells and whose expression progressively declined with age.
The authors postulated that the concomitant decrease in HMGA2 expression and the previously reported increases in INK4A and ARF expression with ageing might indicate that HMGA2 is a negative regulator of INK4A and ARF. They found that INK4A and ARF expression increased in fetal and young, but not old, Hmga2-/- mice. Furthermore, neurospheres cultured from these mice were significantly smaller and produced fewer secondary multipotent neurospheres than wild-type controls, indicating a reduction in their potential for self-renewal. They also observed in vivo phenotypes in the Hmga2-/- mice that were consistent with reduced proliferation of neural stem cells of the central and peripheral nervous systems.
The authors were unable to directly detect HMGA2 binding to the Cdkn2a locus but found that HMGA2 binds to the Junb locus. As JUNB promotes INK4A and ARF expression in stem cells, they speculate that HMGA2 negatively regulates INK4A and ARF by interfering with JUNB expression, although this model will need to be functionally tested. This study highlights an important role for HMGA2 in the regulation of stem cell potential for self-renewal, and is consistent with previous studies that have indicated that HMGA2 functions as a proto-oncogene. This might partly be due to its function as a negative regulator of INK4A and ARF.
Meera Swami
References
Nishino, J., Kim, I., Chada, K. & Morrison, S. J. Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135, 227–239 (2008) | Article | PubMed |
Vescovi, A.L., Galli, R. & Reynolds B. A. Brain tumour stem cells. Nature Rev. Cancer 6, 425–436 (2006) | Article | PubMed |
Scientists Achieve Repair Of Injured Heart Muscle In Lab Tests Of Stem Cells
http://www.sciencedaily.com/releases/2008/11/081125121240.htm
Researchers at Children's Hospital of Pittsburgh of UPMC have been able to effectively repair damaged heart muscle in an animal model using a novel population of stem cells they discovered that is derived from human skeletal muscle tissue.
The research team — led by Johnny Huard, PhD — transplanted stem cells purified from human muscle-derived blood vessels into the hearts of mice that had heart damage similar to that which would occur in people who had suffered a heart attack.
These transplanted myoendothelial cells repaired the injured muscle, stimulated the growth of new blood vessels in the heart and reduced scar tissue from the injury, thereby dramatically improving the function of the injured left ventricle, said Dr. Huard, director of the Stem Cell Research Center at Children's Hospital's John G. Rangos Sr. Research Center.
"This study confirms our belief that this novel population of stem cells discovered in our laboratory holds tremendous promise for the future of regenerative medicine. Specifically, myoendothelial cells show potential as a therapy for people who have suffered a myocardial infarction," said Dr. Huard, also the Henry J. Mankin Professor and vice chair for research in the Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine. "The important benefit of our approach is that as a therapy, it would be an autologous transplant. This means that for a patient who suffers a heart attack, we would take a muscle biopsy from his or her muscle, isolate and purify the myoendothelial cells, and re-inject them into the injured heart muscle, thereby avoiding any risk of rejection by introducing foreign cells."
The myoendothelial cells used in this study were more effective at repairing the injured cardiac muscle and reducing scar tissue than previous approaches that have used muscle cells known as myoblasts, according to Dr. Huard.
At six weeks after injection, the myoendothelial cell-injected hearts functioned at 40 to 50 percent more effectively compared with hearts that had been injected with myogenic cells (myoblasts).
Dr. Huard and colleagues in the Stem Cell Research Center are researching and developing numerous therapeutic uses for the population of muscle stem cells the team identified. One of the most promising uses could be for the treatment of Duchenne muscular dystrophy (DMD), a genetic disease that affects one in every 3,500 boys. Patients with DMD lack dystrophin, a protein that gives muscle cells structure.
Results of this study are published in the Dec. 2 issue of the Journal of the American College of Cardiology.
Stem Cell Research Hold Great Promise, But Obstacles Remain, Expert Argee
http://www.sciencedaily.com/releases/2008/11/081128132025.htm
"There are still a number of major hurdles in the path of stem cell research today that are preventing the routine application of the technology in regenerative medicine." So say UK scientists writing in the International Journal of Biotechnology.
Jane Bower of the ESRC Innogen Centre, at University of Edinburgh, and colleagues highlight some of the recent advances in stem cell science in a new article.
They suggest that research in this area holds promise for applications in regenerative medicine, but point out that technical and ethical remain to be addressed. The researchers also discuss the issue of how to patent stem cell discoveries and to make them commercially viable.
Stem cells are immature cells that can replicate rapidly and then mature into the different cells needed around the body to build tissues in the skin, liver, heart, bone, brain, blood cells, nerves. They are present only in limited quantities in adults but are present in huge numbers in embryonic tissue. Human embryonic stem cells are currently the most promising source for therapeutic purposes, but their use has ethical implications.
Stem cell research holds great promise in medicine.
Advocates hope that the work will lead to important therapies for tackling major degenerative diseases, such as Parkinson's, Alzheimer’s, stroke, heart disease, diabetes, cancer and arthritis. There are also the possibilities of using stem cells to treat debilitating injuries of the spinal cord and other structural injuries. Indeed, the recent case of the trachea engineered to avoid organ rejection by using a patient's own stem cells is a prominent and early success. Stem cells will also have applications in discovering and testing new drugs.
"Technical solutions may involve the use of human embryos and this has created barriers to the use of the technology in a number of countries," Bower and colleagues say, "There is already a need for the progressive development of appropriate legal and regulatory frameworks to allow both the scientific and clinical research to move forward." The team adds that, "Although public acceptability of the technology is by no means universal, it does not at present appear that therapeutic applications are likely to meet with wholesale rejection."
The researchers explain that while there remain technical obstacles to be overcome in stem cell research, Western scientists are not the only ones working on advancing this field. Scientists in China, South Korea, and India are also taking steps forward, although revelations of scientific fraud have led to additional negative publicity.
Nevertheless, the team believes that if a high level of routine success were achieved outside the West, then this might have a positive impact on the public demand for stem cell therapies in the West and so create the political pressure necessary to address the regulatory, legal, and ethical issues sooner rather than later.
hey,, so whats the stem cell play 2day..
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A Joyous, relaxing, fellowship filled Thanksgiving day
to you and yours giving thanks to whom from all
Blessings flow....He makes everything new, He renews,
He restores, He rejuvenates, He reinvigorates, He recreates
life, a life with abundance as He came to prosper us and
to pay the price for our sin.
Do not be anxious about anything, but in everything, by prayer and petition, with thanksgiving, present your requests to God. --Philippians 4:6
Thank you Christ Jesus, our All in All,
*****PL1*****
Obama's Promise on Stem Cells Doesn't Ensure New ‘War’
http://online.wsj.com/article/SB122757360662054989.html
NOVEMBER 25, 2008
By GAUTAM NAIK and ROBERT LEE HOTZ
Some 37 years ago, President Richard Nixon launched a massive, government-led crusade against cancer.
Many U.S. scientists are hoping Barack Obama's new administration will similarly jump-start the nascent but controversial field of human-embryo research to develop treatments for deadly diseases.
Mr. Obama pledged during the campaign to use an executive order to swiftly overturn current federal-funding limits on research into human embryos that are created during fertility treatments. The science is controversial because many people believe destroying an embryo is equivalent to destroying a life.
A relaxing of current restrictions is certain to provide a psychological boost to scientists interested in the field, allowing them to start using expensive equipment funded or partly funded with federal dollars. Some think it may also inspire a round of collaborations between government scientists and those in the private sector and possibly encourage more companies to wade into stem-cell medicine.
"The biopharmaceutical industry has been skittish about making investment in this kind of research. An executive order would give the signal that it's acceptable" to work in this field, says Mary Hendrix, a stem-cell scientist at Children's Memorial Research Center at Northwestern University.
Yet these ambitions depend on the answers to two big questions: How much federal money will be made available for the research? And how quickly can America's major science-funding agency, the National Institutes of Health, take on a leadership role in a field where it has only modest experience and whose funding efforts have lagged behind several state initiatives.
"To make stem-cell science take off, it needs something equivalent to Nixon's war on cancer," says James Thomson, a stem-cell scientist at the University of Wisconsin who created the first human embryonic-stem-cell line in 1998. "But because of today's economic realities, it's not going to happen for at least a couple of years."
Since 1996, a congressional edict has forbidden the use of federal funds to create or destroy human embryos solely for research purposes. In August 2001, President George W. Bush loosened the restriction slightly by allowing federal funds to be used for research on a few then-existing stem-cell lines.
The Obama administration could sidestep the 1996 congressional edict by allowing funding of stem-cell research that employs excess embryos created during privately funded in-vitro-fertilization efforts. The new Congress would have to act independently to lift the public-funding restriction. Any legislative proposal would be virtually certain to renew the fierce political debate over the ethics of human-embryo research.
"We are concerned about the direction the new administration might take, in terms of protecting what we consider to be the sanctity of human life," said Samuel E. Ericsson, president of Advocates International, a Virginia-based Christian legal network that opposes any relaxation of federal restrictions on embryo research.
Many scientists want quick action. The International Society for Stem Cell Research, representing the world's leading stem-cell scientists, has urged Mr. Obama to restore federal funding for embryo research in the first 100 days of his presidency.
While federally funded human-embryo research has been slowed, efforts at private or state-funded laboratories have moved ahead. California's program prompted nine other states to circumvent federal restrictions via local funding initiatives. Earlier this year, New York awarded its first state stem-cell grants from $600 million pledged over the next decade.
So far, California has approved 229 grants totaling $614 million to stem-cell researchers in the state and entered into research agreements with Canada, Australia, the U.K. and Japan. "We are at such a high pace and we have so much funding ourselves that there will be no real competition to our leadership," says Alan Trounson, president of the California Institute for Regenerative Medicine, which heads California's $3 billion state-funded stem-cell program. "The incremental money from NIH will be relatively small because of the economy."
Stem-cell advocates say that while federal restrictions have hurt U.S. pre-eminence in biomedical research, they haven't stopped basic innovation in the field. For example, earlier this year, federally funded Harvard University researchers produced human stem-cell lines for 10 diseases, including diabetes, muscular dystrophy and Parkinson's disease. Privately financed Harvard and Columbia university scientists produced stem cells from the skin of patients with a genetically based disease called amyotrophic lateral sclerosis, or Lou Gehrig's Disease.
Back in 2004, Dr. Hendrix, the stem-cell researcher, moved her human-embryo experiments from Iowa, which had more-restrictive rules, to Illinois. Soon after, Dr. Hendrix testified before an Illinois state senate committee to make the state more stem-cell-friendly. The chairman of that committee was Barack Obama. The state's stem-cell legislation passed in 2005.
"He was pro-stem-cell research then, and he's never changed his position," says Dr. Hendrix...
Stem cells: A new pathway for stem cell ageing and renewal
http://www.nature.com/nrc/journal/v8/n12/full/nrc2547.html
Meera Swami
Stem cells have the potential for self-renewal and are therefore able to persist throughout life in a diverse range of tissues. However, their self-renewing capacity declines with age. What mechanisms are responsible for the differences between young and ageing stem cells? The discovery of a novel pathway involving high-mobility group A2 (HMGA2), INK4A and ARF has recently provided exciting new insights.
Both INK4A and ARF expression increase in ageing tissues, suggesting that a pathway involving these tumour suppressor genes may mediate the differences in self-renewal between old and young stem cells. Sean Morrison and colleagues have now shown that HMGA2, a transcriptional regulator, reduces INK4A and ARF expression in young mice, thus promoting neural stem cell self-renewal. Hmga2 was identified in a full-genome analysis that was carried out by the authors to search for genes that were preferentially expressed in stem cells and whose expression progressively declined with age.
The authors postulated that the concomitant decrease in HMGA2 expression and the previously reported increases in INK4A and ARF expression with ageing might indicate that HMGA2 is a negative regulator of INK4A and ARF. They found that INK4A and ARF expression increased in fetal and young, but not old, Hmga2-/- mice. Furthermore, neurospheres cultured from these mice were significantly smaller and produced fewer secondary multipotent neurospheres than wild-type controls, indicating a reduction in their potential for self-renewal. They also observed in vivo phenotypes in the Hmga2-/- mice that were consistent with reduced proliferation of neural stem cells of the central and peripheral nervous systems.
The authors were unable to directly detect HMGA2 binding to the Cdkn2a locus but found that HMGA2 binds to the Junb locus.
As JUNB promotes INK4A and ARF expression in stem cells, they speculate that HMGA2 negatively regulates INK4A and ARF by interfering with JUNB expression, although this model will need to be functionally tested. This study highlights an important role for HMGA2 in the regulation of stem cell potential for self-renewal, and is consistent with previous studies that have indicated that HMGA2 functions as a proto-oncogene. This might partly be due to its function as a negative regulator of INK4A and ARF.
References and links
ORIGINAL RESEARCH PAPER
Nishino, J., Kim, I., Chada, K. & Morrison, S. J. Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135, 227–239 (2008)
ArticlePubMedChemPortFURTHER READING
Vescovi, A.L., Galli, R. & Reynolds B. A. Brain tumour stem cells. Nature Rev. Cancer 6, 425–436 (2006)
Pluripotent Stem Cells Shown To Generate New Retinal Cells Necessary For Vision, Study Finds
http://www.sciencedaily.com/releases/2008/11/081120210853.htm
(Nov. 21, 2008) — Pluripotent stem cells — those, like embryonic stem cells, that give rise to almost every type of cell in the body — can be converted into the different classes of retinal cells necessary for vision, according to a new study from researchers at SUNY Upstate Medical University.
This research points to exciting new possibilities for preventing or reversing the disabling vision loss caused by age‑related macular degeneration, diabetes retinopathy, retinitis pigmentosa, glaucoma, and other diseases that damage the retina, the layer of light‑sensitive nerve cells that line the back of the eye. The research was presented at Neuroscience 2008, the annual meeting of the Society for Neuroscience in Washington, D.C.
“Vision is lost in these diseases because one or more of the seven retinal cell types die,” said the study’s lead author, Michael Ezra Zuber, Ph.D., assistant professor of ophthalmology and adjunct assistant professor of biochemistry and molecular biology at SUNY Upstate Medical University. “Current treatments can slow these diseases’ progression, but they can’t replace lost retinal cells. Pluripotent cells offer a promising starting point from which to generate new retinal cells.”
Zuber and his colleagues knew that cultured pluripotent cells could be induced to express some retinal cell genes, but they didn’t know if all retinal cell classes could be generated or if the cells would have the ability to form a functioning retina. To test that hypothesis, the scientists turned to pluripotent Xenopus laevis (frog) cells.
Under normal conditions, pluripotent frog cells form only skin tissue. The scientists were able, however, to convert the pluripotent cells to retinal cells by forcing them to express the eye field transcription factor (or EFTF) genes. The reprogrammed cells formed all seven classes of retinal cells normally found in the eyes, including the retinal ganglion cells, which have axons (optic nerves) that extend to the brain.
Furthermore, these new cells eventually formed into functioning eyes. When tested, tadpoles used their induced eyes to detect light and to engage in a vision‑based behavior. The scientists also found a population of self‑renewing cells in the periphery of the induced retinas, suggesting that EFTF‑induced cells also formed adult retinal stem cells.
“The goal of regenerative medicine is to replace dead or dying cells,” said Zuber. “The retina, like all body organs, contains multiple, distinct cell types. Therefore, successful recovery from blindness due to injury or disease will require the functional replacement of multiple retinal cell types. Our results demonstrate that pluripotent cells can be purposely altered to generate all the functional retinal cell classes necessary for vision.”
The research was supported by Research to Prevent Blindness, the E. Matilda Ziegler Foundation for the Blind, The Lions Club of Central New York, and the U.S. National Eye Institute.
Stem cells restore hearing, vision in animals
By Maggie Fox, Health and Science Editor
Wed Nov 19, 2008 6:59am EST
WASHINGTON (Reuters) - Stem cells from tiny embryos can be used to restore lost hearing and vision in animals, researchers said Tuesday in what they believe is a first step toward helping people.
One team repaired hearing in guinea pigs using human bone marrow stem cells, while another grew functioning eyes in tadpoles using frog cells.
While there are no immediate uses for humans, they said their findings help describe some of the most basic biological processes underlying the development of hearing and sight, and may help in the development of the new field of regenerative medicine.
"These discoveries illustrate stem cell research's continuing extraordinary potential to treat a wide range of deadly and disabling diseases that affect millions," said Anand Swaroop, a stem cell researcher at the National Eye Institute, one of the National Institutes of Health.
Dr. Sujeong Jang of Chonnam National University in Gwang-ju, South Korea, and colleagues used mesenchymal stem cells from human bone marrow to restore hearing in guinea pigs whose hearing had been destroyed using chemicals.
They grew the stem cells into neuron-like cells in lab dishes and then transplanted them into the inner ears of the guinea pigs. Three months later, the animals appeared to have some hearing, Jang told a meeting of the Society for Neuroscience.
Jang said the goal was to regrow the tiny hair cells that are essential for mammals to hear, although she is not sure yet how the stem cells made this happen.
They would eventually like to try something similar in humans, Jang told a news conference.
"When sensitive hair cells in the inner ear of humans and other mammals are killed -- by loud noise, autoimmune attack, toxic drugs, or aging -- the damage is permanent," Jang said in a statement.
"Birds and reptiles are luckier. Their damaged hair cells apparently regenerate and can restore normal hearing."
Michael Zuber and colleagues at the SUNY Upstate Medical University in Syracuse, New York, grew functioning eyes in blinded frog embryos using stem cells.
Usually, frog stem cells just form skin when grown in a dish. Zuber's team added seven different genetic "factors" that turned on eye formation genes.
When they transplanted the transformed cells into frog embryos, the resulting tadpoles could see out of those eyes, Zuber told the meeting.
They tested the tadpoles by putting white tissue paper over their tank, Zuber said in an interview. Normal tadpoles will stay in the lighter side of the tank, covered by the white paper.
He showed video of blind tadpoles swimming randomly around the tank while the tadpoles with the transplanted cells stayed on the light side.
Genetic tests showed that the stem cells had transformed, a process called differentiation, into many different cell types.
"All the cells that make an eye are in there," Zuber said.
He does not see any immediate uses for people but noted that regrowing many different cell types is the goal of regenerative medicine.
"The retina, like all body organs, contains multiple, distinct cell types. Therefore, successful recovery from blindness due to injury or disease will require the functional replacement of multiple retinal cell types," he said.
Doctors transplant windpipe with stem cells
http://news.yahoo.com/s/ap/20081119/ap_on_he_me/eu_med_windpipe_transplant
LONDON – Doctors have given a woman a new windpipe with tissue grown from her own stem cells, eliminating the need for anti-rejection drugs. "This technique has great promise," said Dr. Eric Genden, who did a similar transplant in 2005 at Mount Sinai Hospital in New York. That operation used both donor and recipient tissue. Only a handful of windpipe, or trachea, transplants have ever been done.[/b
f successful, the procedure could become a new standard of treatment, said Genden, who was not involved in the research.
The results were published online Wednesday in the medical journal, The Lancet.
The transplant was given to Claudia Castillo, a 30-year-old Colombian mother of two living in Barcelona, suffered from tuberculosis for years. After a severe collapse of her left lung in March, Castillo needed regular hospital visits to clear her airways and was unable to take care of her children.
Doctors initially thought the only solution was to remove the entire left lung. But Dr. Paolo Macchiarini, head of thoracic surgery at Barcelona's Hospital Clinic, proposed a windpipe transplant instead.
Once doctors had a donor windpipe, scientists at Italy's University of Padua stripped off all its cells, leaving only a tube of connective tissue.
[bMeanwhile, doctors at the University of Bristol took a sample of Castillo's bone marrow from her hip. They used the bone marrow's stem cells to create millions of cartilage and tissue cells to cover and line the windpipe.
Experts at the University of Milan then used a device to put the new cartilage and tissue onto the windpipe. The new windpipe was transplanted into Castillo in June.[/b
"They have created a functional, biological structure that can't be rejected," said Dr. Allan Kirk of the American Society of Transplantation. "It's an important advance, but constructing an entire organ is still a long way off."
So far, Castillo has shown no signs of rejection and is not taking any immune-suppressing drugs, which can cause side effects like high blood pressure, kidney failure and cancer.
"I was scared at the beginning," Castillo said in a press statement. "I am now enjoying life and am very happy that my illness has been cured."
Her doctors say she is now able to take care of her children, and can walk reasonable distances without becoming out of breath. Castillo even reported dancing all night at a club in Barcelona recently.
Genden said that Castillo's progress needed to be closely monitored. "Time will tell if this lasts," he said. Genden added that it can take up to three years to know if the windpipe's cartilage structure is solid and won't fall apart.
People who might benefit include children born with defective airways, people with scars or tumours in their windpipes, and those with collapsed windpipes.
Martin Birchall, who grew Castillo's cells at the University of Bristol, said that the technique might even be adapted to other organs.
[b"Patients engineering their own tissues is the key way forward," said Dr. Patrick Warnke, a surgeon at the University of Kiel in Germany. Warnke is also growing patients' tissues from stem cells for transplants.
Warnke predicted that doctors might one day be able to produce organs in the laboratory from patients' own stem cells. "That is still years away, but we need pioneering approaches like this to solve the problem," he said.
Derivation and transcriptional profiling analysis of pluripotent stem cell lines from rat blastocysts
http://www.nature.com/cr/journal/vaop/ncurrent/abs/cr2008301a.html
Received 10 August 2008; Revised 6 October 2008; Accepted 15 October 2008; Published online 4 November 2008.
Abstract
Embryonic stem (ES) cells are derived from blastocyst-stage embryos. Their unique properties of self-renewal and pluripotency make them an attractive tool for basic research and a potential cell resource for therapy. ES cells of mouse and human have been successfully generated and applied in a wide range of research. However, no genuine ES cell lines have been obtained from rat to date. In this study, we identified pluripotent cells in early rat embryos using specific antibodies against markers of pluripotent stem cells.
Subsequently, by modifying the culture medium for rat blastocysts, we derived pluripotent rat ES-like cell lines, which expressed pluripotency markers and formed embryoid bodies (EBs) in vitro. Importantly, these rat ES-like cells were able to produce teratomas. Both EBs and teratomas contained tissues from all three embryonic germ layers. In addition, from the rat ES-like cells, we derived a rat primitive endoderm (PrE) cell line. Furthermore, we conducted transcriptional profiling of the rat ES-like cells and identified the unique molecular signature of the rat pluripotent stem cells.
Our analysis demonstrates that multiple signaling pathways, including the BMP, Activin and mTOR pathways, may be involved in keeping the rat ES-like cells in an undifferentiated state. The cell lines and information obtained in this study will accelerate our understanding of the molecular regulation underlying pluripotency and guide us in the appropriate manipulation of ES cells from a particular species.
Chunliang Li1,4,*, Ying Yang1,4,*, Junjie Gu1,2,3, Yu Ma1,2,3 and Ying Jin1,2,3
1Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine; 225 South Chongqing Road, Shanghai 200025, China;
2Shanghai Stem Cell Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
3Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
4Graduate School of Chinese Academy of Sciences, Beijing 100049, China
Note: Thank you for all the new board marks recently.
It shows that the interest in Stem Cell stocks and
news has been ratcheted up with the new administration
coming into office. Once again, thank you and please
feel free to contribute anything stem cell news related
or even interesting things happening in life as OT.
This board set up by JamaicaBaby, can be the hub of
stem cell news and any and all contributions are very
welcome.
))))PL1((((
Cell Death and Differentiation (2008) 15, 1847–1856; doi:10.1038/cdd.2008.118; published online 12 September 2008
http://www.nature.com/cdd/journal/v15/n12/abs/cdd2008118a.html
Setting the conditions for efficient, robust and reproducible generation of functionally active neurons from adult subventricular zone-derived neural stem cells
Edited by G Melino
Received 14 November 2007; Revised 9 June 2008; Accepted 7 July 2008; Published online 12 September 2008.
Abstract
Although new culture conditions enable homogeneous and long-term propagation of radial glia-like neural stem (NS) cells in monolayer and serum-free conditions, the efficiency of the conversion of NS cells into terminally differentiated, functionally mature neurons is relatively limited and poorly characterized.
We demonstrate that NS cells derived from adult mouse subventricular zone robustly develop properties of mature neurons when exposed to an optimized neuronal differentiation protocol. A high degree of cell viability was preserved.
At 22 days in vitro, most cells (65%) were microtubule-associated protein 2+ and coexpressed -aminobutyric acid (GABA), GAD67, calbindin and parvalbumin.
Nearly all neurons exhibited sodium, potassium and calcium currents, and 70% of them fired action potentials.
These neurons expressed functional GABAA receptors, whereas activable kainate, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartic acid receptors were present in approximately 80, 30 and 2% of cells, respectively. Antigenic and functional properties were efficiently and reliably reproduced across experiments and cell passages (up to 68). This is the first report showing a consistent and reproducible generation of large amounts of neurons from long-term passaged adult neural stem cells. Remarkably, the neuronal progeny carries a defined set of antigenic, biochemical and functional characteristics that make this system suitable for studies of NS cell biology as well as for genetic and chemical screenings.
Keywords: neural differentiation, neural stem cell, adult stem cells, in vitro differentiation, neurones
Abbreviations: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; aNS-1 cell, adult SVZ-derived NS cell; AP, action potential; BDNF, brain-derived neurotrophic factor; Ca2+, calcium; CNS, central nervous system; EGF, epidermal growth factor; FGF-2, fibroblast growth factor 2; GABA, -aminobutyric acid; GAD67, glutamate decarboxylase 1; GFAP, glial fibrillary acid protein; MAG, myelin-associated glycoprotein; MAP2, microtubule-associated protein 2; Na+, sodium; NaV1.2, type 2 voltage-gated sodium channel; NMDA, N-methyl-D-aspartic acid; NS cells, radial glia-like neural stem cells; NSC, neural stem cell; OLIG2, oligodendrocyte transcription factor 2; Pax6, paired box gene 6; RC2, intermediate filament-associated protein RC2; SNAP-25, synaptosomal-associated protein 25; SOX2, SRY (sex determining region Y)-box 2; SVZ, subventricular zone; TTX, tetrodotoxin
D Goffredo1,5, L Conti1,5, F Di Febo2, G Biella2, A Tosoni3, G Vago3, I Biunno4, A Moiana1, D Bolognini1, M Toselli2 and E Cattaneo1
1Department of Pharmacological Sciences and Center for Stem Cell Research, University of Milan, Milan, Italy
2Department of Cellular and Molecular Physiological and Pharmacological Sciences, University of Pavia, Pavia, Italy
3Department of Clinical Sciences 'L Sacco' University of Milan and Pathology Unit, 'L Sacco' Hospital, Milan, Italy
4Department of Medicine, Institute for Biomedical Technologies, National Research Council, Segrate, Milan, Italy
Correspondence: E Cattaneo, Centre for Stem Cell Research and Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy. Tel: +39 02 5031 8333; Fax +39 02 5031 8284; E-mail: elena.cattaneo@unimi.it
5These authors contributed equally to this work and should be considered co-first authors.
Scientists Identify Stem Cells That Can Regenerate Injured Liver Tissue
Thursday, November 13, 2008 - Stem Cell Research News
Linda Greenbaum
http://www.stemcellresearchnews.com/absolutenm/anmviewer.asp?a=1464&z=9
Researchers have discovered a novel protein marker that identifies rare adult liver stem cells, whose ability to regenerate injured liver tissue has the potential for cell-replacement therapy.
For the first time, researchers at the University of Pennsylvania School of Medicine led by Linda Greenbaum, MD, Assistant Professor of Medicine in the Division of Gastroenterology, have demonstrated that cells expressing the marker can differentiate into both liver cells and cells that line the bile duct.
In the future, this marker will allow for the isolation and expansion of these stem cells, which could then be used to help patients whose livers can no longer repair their own tissue.
About 17,000 Americans are currently on a waiting list for a liver transplant, according to the American Liver Foundation.
“In a healthy liver, proliferation of mature liver and bile-duct lining cells is sufficient to maintain the necessary size and function of the organ,” Greenbaum said. “This even works when the liver is confronted with mild and acute injury, but the situation changes when injury to the liver is chronic and severe.”
For chronic injury, the liver uses a back-up system that stimulates stem cells to proliferate and eventually differentiate into new liver cells. Greenbaum and colleagues found that these dual-potential stem cells can be identified and potentially isolated from other liver cells because they uniquely express the protein Foxl1.
The team showed that in two mice models of liver injury, stem cells and their descendents were marked by the expression of FoxL1. The researchers propose to use this marker to isolate the Foxl1-bearing stem cells and transplant them back into damaged livers to restore function.
“At this point, we haven’t identified the molecular targets that are regulated by Foxl1 in the liver stem cell,” Greenbaum said.
The researchers also do not yet know what signals activate the expression of Foxl1 and how exactly it is related to liver function. But, they finally have a molecular handle on identifying liver stem cells, which have remained elusive to scientists.
“This work has significant implications for cell-replacement therapies of chronic liver disease in the future,” Greenbaum said.
The findings are published online this month in the journal Hepatology.
Sticky Post: For news in the Stem Cell sector:
http://www.stemcellresearchnews.com/
http://www.stemcellnews.com/
http://www.sciencedaily.com/news/health_medicine/stem_cells/
PL1
Stem Cell Sciences Reinforces its International Patent Position in Stem Cell Technologies
http://www.foxbusiness.com/story/markets/industries/health-care/stem-cell-sciences-reinforces-international-patent-position-stem-cell-243351246/
IRES Patent Upheld in Appeal Hearing at the EPO
Stem Cell Sciences plc (AIM:STEM, ASX:STC) announces that European patent no. 0695361 covering its IRES technology was upheld by the European Patent Office in Munich on 12th November 2008. The EPO Technical Board of Appeal dismissed objections against the patent raised by Institut Pasteur on 12th April 2007. SCS' IRES (Internal Ribosome Entry Site) technology enables researchers to monitor the activity of a gene of interest in living cells or tissues without blocking the normal function of the gene. In particular, IRES is important for evaluating the success of gene deletions (knock-outs) or insertions (knock-ins) in stem cells, which is crucial for the successful creation of transgenic mouse and rat disease models.
The decision confirms the validity of the patent protection for this technology in Europe and adds value to SCS' current licensing and commercialisation strategy. The Company announced recently its expansion of out-licensing activities for this technology through an agreement with a leading provider of genetically modified rat and mouse models for pharmaceutical research. Furthermore, maintenance of this patent will enable SCS to complete licensing deals held up while potential licensees awaited the outcome of the appeal hearing, generating another source of licensing income.
New UK Patent Granted
The Company also announces today that the UK Intellectual Property Office granted UK Patent 2428041 on 5th November 2008. This new patent covers methods for obtaining cells, especially stem cells, which are particularly useful for drug screening applications and high-throughput assays examining the effects of genes and molecules on stem cell growth. The key step protected by this patent relates to a process known as 'episomal expression' whereby genes of interest remain as free DNA in the cell (an 'episome') rather than being integrated into the chromosome, and this results in more efficient expression of the genes and molecules under assay.
Assays based on this technology were used by scientists at the University of Edinburgh to identify Nanog, a key gene expressed in embryonic stem cells, whose protein product can be used to reprogram adult cells into a pluripotent state (i.e. similar to embryonic stem cells). Technology based on human and mouse Nanog is protected by separate European patents no. 1470155 and 1698639 and is also exclusively licensed to SCS from the University.
Dr Alastair Riddell, CEO of Stem Cell Sciences, said, "Over the past 14 years, Stem Cell Sciences has built an extensive portfolio of intellectual property covering stem cell technologies that may have important application in the discovery and development of new therapeutics. This confirmation of validity of our IRES patent in Europe, which is also granted in the US and elsewhere, as well as this new UK patent, will greatly assist our current discussions with potential licensees to our intellectual property."
About Stem Cell Sciences plc
Stem Cell Sciences (SCS) is an international research and development company focusing on the commercial application of stem cell biology technologies for drug discovery and regenerative medicine research. Stem Cell Sciences is now focussing on building revenues through the sale of products, collaborative research and licensing deals with international biotechnology and pharmaceutical companies.
Stem Cell Sciences has a substantial portfolio of patents and patent applications in both adult and embryonic stem cell fields. The Company has been active in the stem cell research field since 1994, principally focused on technologies to grow, differentiate, and purify adult and embryonic stem cells. These include technologies to permit the generation of highly purified stem cells and their differentiated progeny (specialised tissue cell types) for use in genetic, pharmacological and toxicological screens. Moreover, these technologies may be able to provide pure populations of appropriate cell types for transplantation therapies in the future.
The Company has its main research base and headquarters in Cambridge, UK with a second research base in Monash near Melbourne, Australia and a business development office in San Francisco, USA.
For further information on the company please visit: http://www.stemcellsciences.com.
From the NEJM, a six part series on the Patient/Physician
relationship and the future of medicine. I have it posted
in it's 6 part entirety on The World Medical News Board,
for whomever would care to read this First look from the
NEJM on these subjects...
http://investorshub.advfn.com/boards/board.aspx?board_id=10777
Have an awesome day all,
PL1
Key Mechanism That Regulates Development Of Stem Cells Into Neurons Identified
http://www.sciencedaily.com/releases/2008/11/081110153621.htm
Researchers at the University of Southern California (USC) have identified a novel mechanism in the regulation and differentiation of neural stem cells.
Researchers found that the protein receptor Ryk has a key role in the differentiation of neural stem cells, and demonstrated a signaling mechanism that regulates neuronal differentiation as stem cells begin to grow into neurons. The study will be published in the Nov. 11 issue of the journal Developmental Cell, and is now available online.
The findings could have important implications for regenerative medicine and cancer therapies, says Wange Lu, Ph.D., assistant professor of biochemistry and molecular biology at the Keck School of Medicine of USC, and the principal investigator on the study.
"Neural stem cells can potentially be used for cell-replacement therapy for neurodegenerative diseases such as Alzheimer's and Parkinson's Disease, as well as spinal cord injury," Lu says. "Knowledge gained from this study will potentially help to generate neurons for such therapy. This knowledge can also be used to inhibit the growth of brain cancer stem cells."
During brain development, neural stem cells respond to the surrounding environment by either proliferation or differentiation, but the molecular mechanisms underlying the development of neural stem cells and neurons are unclear, Lu notes.
Ryk functions as a receptor of Wnt proteins required for cell-fate determination, axon guidance and neurite outgrowth in organisms. Researchers at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC analyzed sections of the forebrain in animal model embryos to investigate Ryk's function in vivo.
They found that during neurogenesis, when neural stem cells start to grow into neurons, Ryk protein is cleaved and translocates to the cell nucleus to regulate neuronal differentiation.
This finding is extremely important for understanding the regulation of self-renewal and differentiation of neural stem cells, Lu says. Previous research has shown that Ryk functions as a receptor of Wnt proteins. However, the role of Ryk in neural stem cells and the molecular mechanism of Ryk signaling have not previously been known.
"This study will help in our efforts to produce nerve cells from embryonic stem cells, and may lead to the development of new strategies for the repair of the nervous system, using protein or small molecule therapeutic agents," says Martin Pera, Ph.D., director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.
Further research is needed to explore how Ryk regulates neuronal gene expression, Lu says. Researchers are now expanding their research to studies of differentiation of human embryonic stem cells into neural stem cells and neurons.
These studies are very important for regenerative medicine and drug discovery for therapy of neurodegenerative diseases.
The study was funded by the Baxter Foundation and the American Cancer Society. The current studies using human ES cells are being funded by a CIRM SEED grant.
Journal reference:
Jungmook Lyu, Vicky Yamamoto and Wange Lu. Cleavage of Wnt Receptor Ryk Regulates Neuronal Differentiation during Cortical Neurogenesis. Developmental Cell, Nov. 2008
Obama may reverse Bush policies on stem cells, drilling, abortion..
Reversing executive orders would allow Barack Obama to put stamp on presidency
http://www.cnn.com/2008/POLITICS/11/11/obama.executive.orders/index.html?eref=rss_topstories
Obama vowed in campaign to lift President Bush's restrictions on stem cell research
Obama also may reverse oil drilling decision, "gag order" on family planning groups
Orders to close Guantanamo Bay, Cuba, military prison will take time, aide says
WASHINGTON (CNN) -- President-elect Barack Obama could reverse some of President Bush's most controversial executive orders, including restrictions on embryonic stem cell research, shortly after taking office in January.
President-elect Barack Obama may overturn many of the executive orders that President Bush implemented.
1 of 2 Two other executive orders from Bush -- one dealing with a so-called "gag" order on international aid organizations regarding abortion, the other with oil and gas drilling on federal lands -- also are receiving increased scrutiny.
Obama's transition team is reviewing hundreds of Bush's executive orders, according to John Podesta, Obama's transition co-chair.
New presidents often use executive orders to put their stamp on Washington quickly. Unlike laws, which require months to complete and the consent of Congress, presidents can use their executive authority to order federal agencies to implement current policies.
"Much of what a president does, he really has to do with the Congress -- for example, budgeting, legislation on policy -- but executive actions are ones where the president can act alone," said Martha Kumar of the White House Transition Project, a nonpartisan group established to help new presidential administrations. See what orders Lincoln, Franklin D. Roosevelt, other presidents issued »
Obama is expected to use his executive authority to reverse Bush's order limiting the types of embryonic stem cell research that can receive federal tax dollars.
Advocates for those suffering from a host of diseases -- including diabetes, Parkinson's disease and spinal cord injuries -- are eagerly awaiting the Bush-era restrictions to be lifted.
"We have every reason to believe -- if not on Day One, then in the very near future -- they will be issuing an order rescinding this policy," said Amy Comstock Rick, president of the Coalition for the Advancement of Medical Research.
In August 2001, Bush barred the National Institutes of Health from funding research on embryonic stem cells other than that using 60 cell lines existing when he signed the executive order.
Researchers say the ban has limited their progress and want the opportunity to create new stem cells from human embryos. Many conservatives, however, object to the destruction of human embryos because they believe it ends a human life.
On his campaign Web site, Obama said he supports the creation of new stem cells from embryos created for in vitro fertilization treatments that would otherwise be discarded.
But White House spokeswoman Dana Perino on Monday suggested that the incoming Obama administration should consider keeping Bush's policy in place.
"Unfortunately, the president's position on stem cells has been misconstrued over the years, with the suggestion that President Bush put a ban on research for embryonic stem cell research. That is not true," Perino said. "The president made a very important choice after a lot of careful deliberation."
Other controversial Bush measures Obama is expected to overturn are related to abortion and family planning.
U.S. State Department officials and family planning groups such as Planned Parenthood said they expect Obama to overturn the "Mexico City" policy, first instituted by the Reagan administration. The policy prevents taxpayer dollars from funding groups that perform or promote abortions overseas.
President Clinton dropped the order, but Bush re-implemented it and expanded the policy to ensure State Department funding does not go to family planning organizations that even counsel about abortion.
An Obama administration also could overturn the Bush administration policy of banning funding to organizations such as the U.N. Population Fund that operate in countries that practice forced sterilization, including China, which adheres to the "one child" policy.
Podesta said his team also is reviewing Bush's order that lifted restrictions on oil drilling on fragile federal lands in Utah. Environmental groups decried Bush's decision when he opened the lands to exploration this month, and Podesta called the decision a "mistake."
One set of executive orders that may take longer to overturn pertains to detainees at the Guantanamo Bay, Cuba, military prison.
Obama has said he wants to close the prison, but Denis McDonough, a senior adviser to the incoming Democrat, said Monday that no decisions have been made about what to do with the prison's 255 inmates.
"There is no process in place to make that decision until his national security and legal teams are assembled," McDonough said.
Reversing Bush's executive orders would be an immediate way for Obama to show that a new era has begun in Washington, said Jonathan Turley, a George Washington University law professor.
"Until President Obama gets rid of all these executive orders, he'll be sharing his presidency with his predecessor," Turley said. "Now that's a particularly obnoxious thought for an administration that was elected for change."
LONDON (Dow Jones)--Biotechnology company Stem Cell Sciences PLC (STEM.LN) said this week an Obama presidency is a boon for researchers working in its field.
Alastair Riddell, chief executive of Stem Cell Sciences, told Dow Jones Newswires the expectation is that President-elect Obama will rescind many of the restrictions put in place by his predecessor that limited experiments with stem cells, and stem cells derived from embryos in particular.
"He can't be any more restrictive than George W. Bush," Riddell said.
Stem cells returned to the forefront of biotechnology earlier this month when U.S. biotech Genzyme Corp. (GENZ) unveiled an alliance with stem cell firm Osiris Therapeutics Inc. (OSIR) potentially worth up to $1.5 billion to Osiris.
Really like BCLI as well, Israeli stem cell stock.
Cord Blood Stem Cells May Help Repair Babies' Heart Defects
By Rob Waters
Nov. 10 (Bloomberg) -- Umbilical cord blood, rich in stem cells, may provide raw material to repair the hearts of thousands of babies born each year with defective heart valves, according to researchers.
Cardiologists at the University Hospital of Munich say they are 5 years to 7 years away from transplanting new heart valves into children with faulty hearts, derived from the children's own cord blood. The researchers reported the findings today at the annual meeting of the American Heart Association.
Heart valve abnormalities are one of the most common kinds of inherited heart defects. In these babies, the valves are too narrow or don't close as they should, keeping blood from flowing properly. While surgeons can transplant new valves from human or animal donors, or from artificial material, these valves won't grow as children do, forcing kids to undergo repeated operations to outfit them with new, larger valves, said Ralf Sodian, the cardiac surgeon who led the research.
``Imagine you had a child with congenital heart disease and this child has to be operated on every 2 to 3 years,'' Sodian said in a Nov. 7 telephone interview. ``It's very hard for children and parents. The goal is to do surgery once that would last a lifetime.''
Sodian and his colleagues collected umbilical cord blood from babies as they were being delivered and isolated a key group of stem cells that form the main tissues found in heart valves. After freezing the cells for 12 weeks to preserve them, they seeded those onto a biodegradable polymer scaffold in the laboratory.
The eight bio-engineered valves created by Sodian and his team acted much like natural heart valves when they were tested to see how they would handle blood flow and pressure, he said. The scaffolds will dissolve over time, leaving behind a fully formed structure made from the cells, he said.
Lamb Trial
The next step is to test the procedure by implanting heart valves made in this way into the hearts of young lambs, then watching to see how they grow and function over time, Sodian said. He hopes to begin these experiments next year.
Stem cells from umbilical cord blood, like adult stem cells found in the mature tissues of developed humans, have the potential to form many kinds of cells that can repair or replace damage to organs of the body. Since the umbilical cord stem cells aren't derived from human embryos, they don't raise ethical objections like those that led President George W. Bush to limit federal funding for embryonic stem cells research.
Stem cells from human embryos are more versatile, however, since they are able to form any of the roughly 210 cell types found in the body. Advisers to President-elect Barack Obama said yesterday that Obama may move quickly once he takes office on Jan. 20 to undo the Bush restrictions on embryonic stem-cell research by executive order.
To contact the reporter on this story: Rob Waters in San Francisco at rwaters5@bloomberg.net.
Or - how about this one - BCLI
OSIR-Maryland-based biotechnology firm working on treatments for conditions as varied as Crohn’s disease, knee arthritis, tissue damage, life-threatening Graft-versus-host disease and acute radiation syndrome.
Osiris Therapeutics, Inc. (OSIR) creates therapeutic drugs from human mesenchymal stem cells (MSCs) retrieved from bone marrow donated by healthy adult volunteers.
Bone regeneration = big bucks
Earlier this month, Osiris announced the sale of its Osteocel unit to NuVasive for $85 million.
Osteocel promotes bone regeneration and is used in spinal fusion and other orthopedic procedures.
This deal provides Osiris with the money and ability to focus on the next generation of revolutionary products… products like Chondrogen, which works on the regeneration of knee cartilage, and the multi-purpose Prochymal.
The incredible potential of Prochymal
The most exciting biologic drug in Osiris’ repertoire is Prochymal. Designed to reverse cellular damage, its applications seem limitless.
The most vaunted use is as a treatment for Graft-versus-host disease. Early testing was credited with saving the lives of seven of twelve children in the advanced critical stages of the disease. As a result, the drug is currently in a Phase III trial and has been granted Fast Track status by the FDA.
If all goes as well as anticipated,Prochrymal would be the first approved stem cell therapy in the world.
But it does’t end there…
The positive effects of Prochymal on the gastrointenstinal symptoms of graft-versus-host disease revealed additional prospects.
Osiris has begun a Phase III program using the drug in the treatment of Crohn’s Disease.
Prochymal has also shown results in the repair of heart tissue following a heart attack. In March, Phase I trial results showed patients receiving the drug had markedly less cardiac arrythmias as well as significant improvements in heart and lung function.
The Department of Defense has bought into this technology
In January, Osiris, partnered with Genzyme, was awarded a $224.7 million contract by the Department of Defense to develop and stockpile Prochymal for the treatment of gastrointestinal injury resulting from acute radiation syndrome.
This opens the company up to a whole new client sector.
Like many research-focused biotechs, Osiris operates at a net loss. For the first quarter of 2008, the loss amounted to $15.6 million – that’s up from $11.5 million the year prior.
The main reason for this increase is the additional research and testing involving Prochymal.
The first-quarter report listed an available cash flow of $42 million and a credit line of $30 million through its primary backer, Friedli Corporate Finance.
A sound investment
Some estimate that the market for stem cell therapy to be around $20 billion by 2010.
Besides the opportunities presented by Prochymal, Osiris has 47 patents for their cutting-edge technology in the U.S. and over 200 foreign patents owned or licensed.
Osiris Completes Enrollment of Stem Cell Trial to Treat Pulmonary Disease
Tuesday September 23, 9:30 am ET
COLUMBIA, Md.--(BUSINESS WIRE)--Osiris Therapeutics, Inc. (NASDAQ:OSIR - News) announced today that it has completed enrollment in a human clinical trial designed to evaluate Prochymal, the Company’s proprietary formulation of adult mesenchymal stem cells, for the treatment of moderate to severe Chronic Obstructive Pulmonary Disease (COPD). A total of 62 patients were enrolled in the Phase II trial at six sites throughout the United States.
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“These stem cells have qualities that make them naturally well suited for the repair of lung tissue, and early clinical data are so far very encouraging,” said Michelle LeRoux Williams, Ph.D., Vice President of Development at Osiris Therapeutics. “We are excited to learn more about the therapeutic utility of these cells in the lungs, not only for the treatment of COPD, but for other pulmonary conditions as well. This study will provide for us the necessary base for further rapid development of this remarkable stem cell technology in what could ultimately prove to be a broad spectrum of lung diseases.”
Mesenchymal stem cells have been shown to be effective in treating numerous lung diseases in pre-clinical animal models. The ability of the stem cells to reduce inflammation, block fibrosis or scarring and repair tissue damage suggests that they may be effective in reversing or preventing the progression of COPD. In an earlier human trial for heart disease, infusions of Prochymal were shown to improve lung function by a statistically significant margin compared to patients receiving placebo.
“We would like to thank our participating physicians and their teams for the remarkable job they did enrolling this study so quickly,” said Robin Flannery, who coordinated the trial at Osiris. “But most of all, we would like to recognize and offer our sincere thanks to the patients who are participating in this historic trial. It is only with their cooperation that we seek to usher in a new era in the treatment of lung disease.”
Osiris is investigating Prochymal in patients with COPD, the fourth leading cause of death in the United States. Over 12 million Americans have been diagnosed with the disease, and it is estimated that an additional 14 million Americans have the disease and have not yet been diagnosed.
About the Phase II Chronic Obstructive Pulmonary Disease Trial
The Phase II trial is evaluating the safety and efficacy of Prochymal in conjunction with standard of care for improving pulmonary function in patients with moderate to severe COPD. The clinical trial is a double-blind, placebo-controlled study. Patients were randomized to either Prochymal or placebo at a 1:1 ratio. Measurements used in the trial to detect potential improvements in subjects treated with Prochymal include pulmonary function tests, exercise capability, and quality of life assessments. In addition, exacerbations and hospitalizations due to COPD will be monitored for both safety and efficacy. Patients will be evaluated over the course of two years following initial Prochymal or placebo infusion.
About Prochymal
Prochymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors, avoiding the controversy surrounding embryonic and fetal cell sources. Prochymal is currently being evaluated in three, double-blind, placebo controlled Phase III studies, including steroid refractory GvHD, acute GvHD, and Crohn’s disease. Prochymal has been granted Fast Track status by FDA for all three of these indications. Prochymal also obtained Orphan Drug status by FDA and the European Medicines Agency for GvHD. Prochymal is also being studied in Phase II trials for the treatment of acute myocardial infarction and type 1 diabetes. Additionally, the Department of Defense recently awarded Osiris a $224.7 million contract to develop Prochymal as a treatment for acute radiation syndrome.
About Osiris Therapeutics
Osiris Therapeutics, Inc. is a leading stem cell therapeutic company focused on developing products to treat medical conditions in the inflammatory, orthopedic and cardiovascular areas. Prochymal is being evaluated in Phase III clinical trials for three indications, including acute and steroid refractory Graft versus Host Disease and also Crohn's disease, and is the only stem cell therapeutic currently designated by FDA as both an Orphan Drug and Fast Track product. Osiris also has partnered with Genzyme Corporation to develop Prochymal as a medical countermeasure to nuclear terrorism and other radiological emergencies. Furthermore, Prochymal is being developed for the repair of heart tissue following a heart attack, the protection of pancreatic islet cells in patients with type 1 diabetes, and the repair of lung tissue in patients with chronic obstructive pulmonary disease. The Company’s pipeline of internally developed biologic drug candidates under evaluation also includes Chondrogen for arthritis in the knee. Osiris is a fully integrated company, having developed capabilities in research, development, manufacturing, and distribution of stem cell products. Osiris has developed an extensive intellectual property portfolio to protect the company's technology including 47 U.S. patents each having one or more foreign counterparts. Osiris, Prochymal and Chondrogen are registered trademarks of Osiris Therapeutics, Inc. More information can be found on the company's website, www.Osiris.com. (OSIR-G)
Osiris shares rocket on Genzyme pact
By Val Brickates Kennedy
Last update: 12:07 p.m. EST Nov. 4, 2008
BOSTON (MarketWatch) --Osiris Therapeutics (OSIR:
OSIR 17.71, +0.16, +0.9%) shares shot up 15% to $17.85 Tuesday on news that it has struck a potentially lucrative deal with Genzyme Corp. The stem cell researcher said it has entered it a partnership with Genzyme (GENZ:
GENZ
GENZ, , ) to develop two of its stem cell treatments, Prochymal and Chondrogen, for a variety of disorders. Under the agreement, Osiris will commercialize the products in the U.S. and Canada, while Genzyme will market the products overseas. Osiris will receive $130 million upfront, and could earn up to $1.25 billion in milestone payments from Genzyme if certain goals are met. Shares of Genzyme were up 2% at $74.98.
Stem-cell Sentry Sounds The Alarm To Maintain Balance Between Cancer And Aging, Researchers Find
http://www.sciencedaily.com/releases/2008/10/081015144127.htm
Like a sentry guarding the castle walls, a molecular messenger inside adult stem cells sounds the alarm when it senses hazards that could allow the invasion of an insidious enemy: Cancer.
The alarm bell halts the process of cell division in its tracks, preventing an error that could lead to runaway cell division and eventually, tumor formation.
"Our work suggests that to be able to prevent abnormal cell proliferation, which could lead to cancer, stem cells developed this self-checking system, what we're calling a checkpoint," said Yukiko Yamashita of the University of Michigan's Life Sciences Institute.
"And if it looks like the cell is going to divide in the wrong way, the checkpoint senses there's a problem and sends the signal: 'Don't divide! Don't divide!'" said Yamashita, a research assistant professor of life sciences and an assistant professor of cell and developmental biology at the U-M Medical School.
If everything looks OK, the checkpoint allows adult stem-cell division to proceed, providing new cells to replace damaged and worn-out tissues.
Yamashita and her colleagues have not yet identified the molecules that form the checkpoint mechanism. But they've seen it at work in adult stem cells of the fruit-fly testes, so-called germ-line stem cells.
"Aging is too few divisions and cancer is too many divisions, and people have long speculated that some process controls the balance between them," Yamashita said. "We may have found the mechanism that maintains the delicate balance between over-proliferation---which can lead to cancer---and aging."
If humans possess a similar checkpoint system and if researchers could someday harness it, they could fine-tune the rate of cellular division to control tumor development as well as tissue aging. But Yamashita stressed that no mammal studies of the checkpoint have been undertaken, so talk of potential human applications is highly speculative.
In fruit flies, the checkpoint monitors germ-line stem cells as they're about to divide. It can sense problems that would derail the division process, which is called mitosis.
Under normal conditions, adult stem-cell division creates one new stem cell and one cell committed to develop into a specific tissue type – such as a skin cell, a blood cell or, in this case, a sperm cell. That form of mitosis is called asymmetric division, and it's exactly what stem cells need to maintain a healthy balance between uncommitted and committed cells.
Cell division is controlled in part by the location of a pair of cellular components called centrosomes. They provide the framework that helps direct how chromosomes are distributed between daughter cells during mitosis.
Normally, centrosomes in a dividing stem cell remain perpendicular to an adjoining messenger cell called the hub. Yamashita and her colleagues found that improper orientation of the centrosomes disrupts the mitotic machinery, steering it on a course toward stem-cell over-proliferation and cancer.
The checkpoint mechanism senses when centrosomes are misaligned, then sounds the alarm that stops cell division.
By preventing faulty cell division, the checkpoint helps ward off cancer. But a balance must be struck: If the checkpoint mechanism slows cell division to a trickle, the resulting shortage of new cells will accelerate tissue aging.
"It's a double-edged sword, and both outcomes are bad," she said. "One path leads to cancer and the other leads to aging. And we haven't found a way to avoid aging without getting cancer."
The team's findings will be published Oct. 15 in the online version of the journal Nature. The first author is Jun Cheng of the U-M Department of Biomedical Engineering. Other authors are Nezaket Turkel and Nahid Hemati of the Life Sciences Institute, Margaret Fuller of Stanford University and Alan Hunt of the U-M biomedical engineering department.
The work was supported by a U-M startup fund, the March of Dimes Basil O'Conner Starter Scholar Research Award, the Searle Scholar Program, and the National Institutes of Health.
OSIR-Genzyme, Osiris Eye Stem Cell-Based Drugs
Friday November 7, 6:10 pm ET
Peter Benesh
At last, there's evidence that some companies are getting close to commercializing stem cell science.
Last week Genzyme (NasdaqGS:GENZ - News) and Osiris Therapeutics (NasdaqGM:OSIR - News) announced a pact that could be worth $1.4 billion, assuming all expectations and milestones are met.
It's the largest deal ever in the young stem cell industry, says Randal Mills, president and chief executive of Osiris. "It gives us a monumental influx of resources and tells the world that stem cell therapy has arrived."
Osiris has two stem cell-based products: Prochymal and Chondrogen. The Genzyme deal is aimed at getting regulatory approval for both and getting them to market.
Prochymal is in a pair of phase three trials. The first is for graft vs. host disease, a life-threatening immune condition that can hit cancer patients after a bone marrow transplant.
The second is for Crohn's disease. Crohn's is a chronic inflammatory disease of the intestines, afflicting more than 500,000 patients in the U.S. It requires the removal of bowel sections in 50% of patients.
Prochymal is also in clinical trials for the treatment of chronic obstructive pulmonary disease. With 12 million Americans diagnosed, it's the No. 4 cause of death in the U.S. And the drug is in clinical trials for prevention of heart failure after heart attack as well as a treatment for type 1 diabetes.
Chondrogen will soon start a phase two/three trial for regeneration of the meniscus in the knee, and prevention of osteoarthritis.
Opportunity Knocks
Financing Osiris' stem cell technology fits Genzyme's strategy and timetable, says David Meeker, a medical doctor and Genzyme's executive vice president for therapeutics, biosurgery and transplant.
"We like to invest in late-stage opportunities, while there's still an opportunity for us to create value," Meeker said.
Genzyme will make two upfront payments to Osiris: $75 million right away and $55 million on July 1, 2009. With milestones and royalties, Genzyme could pay Osiris another $1.25 billion.
Under the deal, Osiris will handle sales in the U.S. and Canada, while Genzyme will market Osiris' stem cell drugs in the rest of the world, paying royalties to Osiris.
Osiris will pay for the current rounds of clinical trials and for new trials for new uses of the drugs through phase two. Osiris and Genzyme will share the cost of phase three and four trials, with Osiris paying 60% and Genzyme 40%.
Those payments will give Osiris its first yearly profit since its founding in 1992. Thomson Reuters analysts expect earnings of $2.59 a share for 2008, though next year they see a loss of 5 cents.
Osiris' stock rose as much as 27% on Nov. 4, the day the deal was announced, before closing up 2.8%. Shares currently trade near 18, up from 11 the week before the deal.
Shares of Genzyme rose 1.4% to 74.60 the day of the deal, though they've since slumped and now trade near 71.
Wall Street Pitch
Genzyme's research spans many technologies, including protein, antibody, polymers, cells, genes, bio-materials and chemical-based drugs. The company targets rare inherited disorders, kidney disease, orthopedics, transplant, cancer and diagnostic testing.
Osiris' stem cells come from bone marrow of adult donors. The cells are encouraged to multiply in the lab. A small sample can become 10,000 cells, Mills says.
The deal should awaken investors to stem cell possibilities, says William Tanner, an analyst with Leerink Swann. "Stem cell therapies have not been ready for prime time, but if this technology works, it will underscore the importance of stem cells for treatment of various diseases."
Another benefit is that there's a natural synergy between Osiris and Genzyme. That's partly because the two firms have already worked together. They've been partners in a $225 million Department of Defense project to develop Prochymal to treat acute radiation syndrome, which results from nuclear attack or accident.
Still, both face challenges making the latest collaboration a success, watchers say.
"They must show efficacy and safety, and it's unclear how these stem cell drugs will respond in phases two and three," said analyst Matthew Osborne of Lazard Capital.
Meanwhile, there is talk that Genzyme, with a market cap of $19 billion, might decide to buy Osiris, which has a market cap of less than $500 million.
Genzyme might have to pursue an acquisition to take advantage of Osiris' U.S./Canadian rights to Prochymal and Chondrogen. Though Genzyme gets rights to the rest of the world, "there's practically no market outside the U.S.," Tanner said. To maximize its investment, "Genzyme will have to buy these guys."
If Genzyme does make a buyout offer, Tanner reckons it will come before the end of 2010.
Lazard's Osborne offers a different view. He says Genzyme "makes deals based more on licensing than acquisition." Since buyouts are expensive, he adds, Genzyme will stick with licensing to keep its commitment to 20% annual earnings growth.
Rainmaker, hello....post some info on this company first please so that others may see what you are talking about
and asking for....TIA....
PL1
You might want to add some info on OSIR to the ibox and board. This will be the first one to get an FDA approved treatment using stem cells. Phase 3 fast track already. Genzyme just ponied up 1 billion deals plus to get in bed with OSIR.
Stem-cell firms surge as Obama fuels funding hopes
Mon Nov 10, 2008 7:01pm EST
http://www.reuters.com/article/vcCandidateFeed2/idUSTRE4AA00920081111?sp=true
BANGALORE (Reuters) - Shares of companies developing therapies based on stem cells surged on Monday, after confirmation over the weekend that U.S. president-elect Barack Obama plans to reverse an existing executive order against federal funding of embryonic stem-cell research.
Companies such as Geron Corp and StemCells Inc saw a sharp rise in their stock price as investors rushed to be a part of a field that holds significant commercial potential.
"People now know what the future executive landscape is going to look like, and they are trying to figure out how to profit from it," WBB Securities analyst Steve Brozak said.
Stem cells are the body's master cells, giving rise to tissues, organs and blood. Scientists hope to harness their power to transform medicine, to repair devastating injuries, replace the brain cells lost in Parkinson's disease, cure juvenile diabetes, or treat diseases such as Alzheimer's.
But research related to embryonic stem cells has been under political scrutiny for a long time due to ethical issues, as it involves the destruction or manipulation of human embryos.
Republican President George W. Bush had vetoed bills to expand federally funded embryonic stem-cell research, and showed a preference toward adult stem-cell research that is considered more ethical by many conservative voters.
Among the several types of stem cells, embryonic stem cells, derived from days-old embryos, are considered to hold the most potential as they can give rise to all the cell types in the body. But applications for adult stem cells are considered limited as they do not live in the body for long.
A reversal of President Bush's long-standing policy, which restricts funding for stem-cell research, by Democrat Obama would give a boost to companies seeking to develop therapies based on that research.
Several stem-cell focused companies reported positive developments on Monday.
Geron said its potential HIV treatment, TAT2, had promising preclinical data, while biotech giant Celgene Corp got a regulatory nod to go ahead with human trials of its experimental stem-cell therapy for the treatment of Crohn's disease.
"We will see more and more of these events just given the fact that there is more and more path for the commercialization of stem cells -- adult, placental, umbilical and now, more embryonic," WBB's Brozak said.
Shares of Geron were up as much as 16 percent, while StemCells' shares soared 42 percent. Both stocks have risen significantly over the last one month.
Other smaller players in the field also benefited.
Shares of Aastrom Biosciences Inc, which have jumped 170 percent over the last month through Friday, were trading up 26 percent on Nasdaq.
Tiny companies like Neuralstem Inc, NeoStem Inc and BioHeart Inc also saw a spike in their share price.
Stem cell heart cure to be tested
http://news.bbc.co.uk/1/hi/health/4326698.stm
Different therapies will be tested
Doctors have launched a trial to test whether heart disease can be treated using a patient's own stem cells.
The study, at Barts and the London NHS Trust, is funded by a charity set up by a man who underwent stem cell treatment for his heart condition in Germany.
The aim will be to determine whether adult stem cells taken from bone marrow can repair damaged heart muscle.
In total, 700 patients will take part in the study, which will test three different forms of stem cell therapy.
STUDY VOLUNTEER
Gerry Sherrick, 71, a retired taxi driver from Essex has had two heart attacks and two triple bypass operations.
He said: "My heart has become steadily weaker over the years. I now struggle to do many of the things I could do before. Mundane tasks like getting washed, eating and even lifting up a newspaper can leave me feeling completely exhausted.
"I have my good days but on others it can be a struggle just to get out of bed."
The first part of the study will involve 300 patients whose hearts are failing because of heart disease or a previous heart attack.
A second arm will involve 200 patients whose hearts are failing specifically because of dilated cardiomyopathy - a heart muscle disorder.
And a final element will involve 200 patients who have just had a heart attack.
Some patients will have stem cells extracted from bone marrow in their hip and injected into their major coronary arteries or directly into their heart.
Others will receive injections of growth factor drugs to try to cause stem cells to spill out of their bone marrow and into their blood without the need for the operation.
Huge potential
Lead researcher Dr Anthony Mathur said: "This is one of the biggest and most comprehensive trials of its kind in the world.
Ian Rosenberg has benefitted from stem cell therapy
"Our studies will tell us if adult stem cells in bone marrow can repair damaged hearts and if so how these cells should be administered to patients.
"There is growing evidence to suggest that stem cells may benefit people with serious heart conditions, such as heart failure or those who have had heart attacks."
Stem cells are the body's master cells, with the ability to turn into almost any type of cell in the body.
Dr Mathur said harnessing the cell's potential to repair damaged heart muscle good be good news for the 2.7m people with heart disease in the UK.
He said: "If proven to work, these cells could revolutionise the way we treat heart disease and could transform the lives of millions of people not only in the UK but around the world."
The work is being funded by a new charity, the Heart Cells Foundation, set up by Ian Rosenberg.
Two years ago doctors told Mr Rosenberg his heart disease was so severe that he had just a couple of months to live.
He travelled to Germany, were stem cells were injected into his heart.
"Within a matter of months, I was able to do things I could only dream of doing before, such as walking up and down stairs or playing golf," he said.
"Stem cell therapy has given me years I never thought I would have.
"I set up the Heart Cells Foundation so that others may benefit from this new and exciting science."
So far the charity has raised £1m to fund the Barts' research. However, another £5m will be needed over the next four years.
Peter Weissberg, of the British Heart Foundation, said stem cell therapy had the potential to revolutionise the treatment of heart disease.
However, he said much work was needed to determine whether the therapy was safe as well as effective.
People interested in taking part in the clinical trial can get more information by calling 020 8983 2216, or by emailing laura.roberts@bartsandthelondon.nhs.uk.
Thank you Rainmaker and welcome to the Stemware board...
Have an awesome day and come back and post as well...
PL1
Great board have it marked....very nice work
Obama reviews Bush orders on stem cells, drilling
Nov 9, 11:11 AM (ET)
By STEPHEN OHLEMACHER
WASHINGTON (AP) - President-elect Obama's transition chief said Sunday the incoming administration is reviewing President Bush's executive orders on stem cell research, oil and gas drilling and other matters.
John Podesta said the president can use such orders to move quickly without waiting for Congress to act, highlighting the extraordinary powers a president can wield beyond signing legislation approved by Congress. Podesta said people should expect Obama to use those powers to reverse many policies of the Bush administration.
"I think across the board, on stem cell research, on a number of areas, you see the Bush administration even today moving aggressively to do things that I think are probably not in the interest of the country," Podesta said in a broadcast interview.
"There's a lot that the president can do using his executive authority without waiting for congressional action, and I think we'll see the president do that," Podesta said.
President Bush has limited federal spending on stem cell research, a position championed by opponents of abortion rights. Obama has supported the research in an effort to find cures for diseases such as Alzheimer's.
Also, the federal Bureau of Land Management is opening about 360,000 acres of public land in Utah to oil and gas drilling, leading to protests from environmentalists.
"They want to have oil and gas drilling in some of the most sensitive, fragile lands in Utah," Podesta said. "I think that's a mistake."
Podesta also said Obama is working to build a Cabinet that is diverse. That includes reaching out to Republicans and independents - part of the broad coalition that supported Obama during the race against Republican John McCain.
A top House Republican said there is a willingness to try to work with Obama to get things done. But Rep. Eric Cantor also said to expect Republicans to serve as a check against the power held by Obama and House Speaker Nancy Pelosi, a Democrat from California.
"There is going to be, I think, a willingness to try and get things done," Cantor said. "But at the end of the day I think you will see a Republican Party in Congress serving as a check and a balance against Mr. Obama's power and Speaker Pelosi's power."
Cantor, a Virginia Republican, is running to be the second-ranking Republican in the House - the job of minority whip.
Cantor and Podesta spoke on "Fox News Sunday."
http://www.nature.com/stemcells/2008/0810/081030/full/stemcells.2008.138.html
In search of a viable business model
Heidi Ledford1
Stem cell companies evolve to meet the demands of investors, partners and customers
When Alan Lewis left Celgene, a publicly traded pharmaceutical company worth nearly $15 billion at the time, to become chief executive of Novocell, a struggling stem cell company based in San Diego, California, he had to make a few lifestyle adjustments. "Before it was like staying at the Four Seasons Hotel," he says. "This is like the El Cheapo on the corner."
Lewis had decided he wanted to work for a stem cell company in the excitement following the passage in 2004 of Proposition 71, the $3-billion California stem cell initiative. As soon as he arrived at Novocell in 2006, Lewis got to work raising money —and tightening the budget. He closed Novocell's Irvine, California site, and pared down the company's staff. Novocell narrowed its scientific goals, dropping several projects to focus on the aim of producing insulin-producing cells from human embryonic stem (ES) cells for use as a treatment for diabetes. "In the last year or so we've been really putting virtually all of our eggs in that basket," he says.
Risky business
Early-stage biotechnology is always risky, and it has been a particularly tough road for stem cell companies. The industry has struggled under burdensome regulations, unreasonable expectations, and increasingly conservative venture capitalists, while trying to push forward an untested form of therapy that everyone knows will be expensive to implement. But some who started out in the early days of the stem cell industry say the financial climate is getting warmer. "The market is now starting to awaken," says Johan Hyllner, who has worked for the Swedish stem cell company Cellartis in Gøteborg since 2001.
By industry standards, Novocell is doing well in many ways. Privately owned and venture-capital backed, about 30% of the company's funding comes from Johnson & Johnson Development Corporation, the venture-capital arm of New Jersey-based pharmaceutical giant Johnson & Johnson. Collaborations with the pharmaceutical industry have historically been rare for stem cell companies, but the industry has lately been investing in the field. Earlier this year, UK-based GlaxoSmithKline announced a $25-million investment in Harvard University's Stem Cell Institute with the aim of harnessing stem cell technology for drug screening and Roche teamed up with Wisconsin stem cell company Cellular Dynamics International to use cardiac cells derived from ES cells to test drug candidates for toxicity. In 2007, Merck licensed neural stem cell technology from Stem Cell Sciences in Cambridge, United Kingdom, also for drug screening.
Although these investments are tiny relative to the large research and development budgets of the pharmaceutical industry, the industry is warming to stem cells, says Ruth McKernan, chief scientific officer of Pfizer Regenerative Medicine in Cambridge, UK. When she attended a Keystone meeting on stem cells in 2005, almost no one else from the pharmaceutical industry was there, she says. "Now, every meeting I go to I see more of my colleagues from pharma than I saw at the meeting before."
Pfizer is investing "a significant amount" of money to establish a regenerative medicine programme and intends to commit about 70 employees to the group, says McKernan. The programme will look for small molecules that alter cell fate and differentiation by, for example, screening for compounds that stimulate neurogenesis in the brain. Pfizer will stop short of using stem cells directly for therapy, but McKernan hopes the information her group will generate about how to control stem cells will help the company prepare for future work in that direction.
Therapy on hold
Developing therapies is far riskier and costly than developing research tools. Consequently, pharmaceutical companies and other investors remain hesitant to back such projects; Johnson & Johnson's investment in Novocell's therapeutic project is unusual. Some companies have opted out of the therapeutics business altogether. Cellular Dynamics, for example, has been focused from the start on drug screening and toxicity testing — two areas with immediate application and of significant interest to pharmaceutical companies — and also provides a profitable drug-testing service that is not based on stem cells. "We're starting with drug screening because we understand that market," says Nicholas Seay, chief technology officer at the company. "We're not talking about therapeutics." Other companies, like Cellartis, began with a focus on therapeutics and then became a stem cell provider when confronted with market realities. "Within a year we realized we had to focus," says Hyllner. "We had to do all of these steps anyway to get a therapy. We figured we might as well try to get mid-term revenues as well."
But some early clinical trials have looked promising. Osiris Therapeutics in Columbia, Maryland, is testing preparations of adult mesenchymal stem cells collected from the bone marrow of healthy volunteers and then purified and cultured. Its product, under the trade name Prochymal, has reached a phase III trial for use in acute graft-versus-host disease, and earlier-stage clinical trials are under way for its use in heart failure, lung disease, Crohn's disease and more.
Other companies pushing stem cells into therapy have suffered setbacks. Geron, in Menlo Park, California, wanted its treatment for spinal cord injury to be the first ES-cell-derived treatment to enter clinical trials, but the company has been in limbo since May this year, when the US Food and Drug Administration (FDA) placed the trial on 'clinical hold' while the agency grapples with how to handle a therapy unlike any it has dealt with before. (See Embryonic stem-cell trial put on hold.)
Earlier this year, Advanced Cell Technology (ACT), headquartered in Los Angeles, California, was in talks with the FDA about clinical trials to test retinal pigment epithelium cells derived from ES cells as a treatment for age-related macular degeneration. Then in July the company announced that it was almost broke, research ground to a near standstill, and the company is scrambling to find new investors. ACT has had such problems before: "This is something that's probably happened five to six times," says chief scientific officer Robert Lanza. "We hear all of this excitement about the promise of stem cells," he says. "In reality, there's virtually no money."
A few years ago, ACT opened a facility in Alameda, California, and announced that the company hoped to take advantage of Proposition 71 funds. "That never really panned out," says Lanza. "The money was held up by court challenges and never went to companies." ACT closed the site to save money in September, and consolidated its research programme in its original home of Worcester, Massachusetts. Since then, the California Institute of Regenerative Medicine — the administrator of Proposition 71 funds — has announced intentions to launch a loan programme for stem cell biotechnology companies that would distribute about $500 million over 8-10 years.
Venture capital cautious
Since the technology bubble burst, venture capitalists have grown more cautious, investing almost exclusively in late-stage biotechnology companies that are already in clinical trials. Few stem cell companies can meet those standards, and the squeeze is expected to get even tighter as countries rush to ease the flow of funds and credit through banking systems. "Regenerative medicine and cell-based therapy is not heavily supported by the venture community," says Arnold Caplan, a biology professor at Case Western Reserve University in Cleveland, Ohio, and a co-founder of Osiris Therapeutics.
"Regenerative medicine and cell-based therapy is not heavily supported by the venture community," says Arnold Caplan
A few boutique venture-capital firms, such as Toucan Capital based in Bethesda, Maryland, have opened with the explicit goal of funding stem cell and regenerative medicine technologies. California-based Proteus Venture Partners, headed by Gregory Bonfiglio, also has plans to raise a dedicated fund for investing in regenerative medicine companies. Bonfiglio says that some of his colleagues think he's "nuts" for targeting early-stage stem cell companies. "But I do think that attitude is changing," he adds. Proteus Venture Partners is three years old, and, financial crisis notwithstanding, aims to build its fund to $300 million by the first half of 2009. That will not be enough cash to carry early-stage companies through to the end of their clinical trials, but Bonfiglio hopes other investors will eventually step in.
Jonathan Gertler, who heads investment banking in biotechnology for Leernik Swann in Boston, agrees that attitudes are changing, but says money isn't flowing yet. "There's increasing interest in monitoring the space by financial investors, but monitoring isn't investing." Reached a few days after several governments announced unprecedented steps to restore liquidity, Gertler said he expected to see a "groundswell of support" for stem-cell ventures within the next couple of years.
Some stem cell companies have already managed to tap into venture funding. Cellular Dynamics, which was co-founded by University of Wisconsin-Madison stem cell researcher James Thomson, founded the company with cash from a local venture-capital fund called Tactics II Ventures, which created a designated stem cell programme specifically to gather funds for the company.
While companies whose technology is based on ES cells struggle for cash, companies based on induced pluripotent stem (iPS) cells seem to be viewed more favourably by investors. Inevitable conflicts over intellectual property loom on the horizon and there are still technical hurdles to overcome. Nonetheless, investors are happy to be freed from the entanglements of work with embryos. iZumi Bio in Mountain View, California, a company founded to generate therapies from iPS cells, received venture funding from Kleiner Perkins Caufield & Byers, the firm that arguably launched the biotech industry by financing Genentech. And Fate Therapeutics, based in Seattle, Washington, has garnered backing from prominent firms including Arch Venture Partners, which has a branch in Seattle, and Polaris Venture Partners of Boston, Massachusetts, to fund its plan to stimulate and reprogramme adult stem cells using small molecules.
Pfizer's McKernan credits the advent of iPS cells for whetting the pharmaceutical industry's appetite for stem cell technology, since they can be made without embryos.
Nonetheless, iPS cells could fall victim to the same hype that plagued the early days of ES cell research. But regardless of where the stem cells come from, the industry is yearning for a therapeutic victory. "What we really, urgently need is a big success," says Lanza. And for all the uncertainty, Lewis is glad he made the switch to Novocell. "You get used to sort of the rich life of being in a fat cat pharma, but it isn't so bad to slim down a little bit and use your money wisely. That doesn't mean that it's any less exciting."
Author affiliations
1. Heidi Ledford writes for Nature from Boston
Michigan ad likens stem-cell work to Tuskegee study
http://news.yahoo.com/s/ap/20081023/ap_on_re_us/ballot_stem_cell_ad;_ylt=AkxvAteFSpvdgrU13d7vsdjVJRIF
By DAVID EGGERT, Associated Press Writer David Eggert, Associated Press Writer – Thu Oct 23, 2:36 pm ET Reuters –
An undated image showing mouse embryonic stem cells stained with a flourescent green marker.
(National … LANSING, Mich. – A television ad created by opponents of a ballot measure that would allow embryonic stem-cell research in Michigan likens such work to the infamous Tuskegee syphilis study.
The ad, which began running Tuesday in the Detroit, Flint, and Saginaw areas, shows newspaper headlines and other references to the Tuskegee study.
In the study by the U.S. Public Health Service in Tuskegee, Ala., poor, black men with syphilis weren't told they had the disease and were denied treatment when penicillin became available in the 1940s. The widely criticized study ended in 1972.
Proposal 2 on the November ballot would change the state constitution to allow people to donate embryos left over from fertility treatments for scientific research.
"Unfortunately, unrestricted science has had an ugly past," the announcer warns, "and it's been unfairly applied to the vulnerable and minorities. Proponents of Proposal 2 are now seeking the right to conduct unregulated scientific experimentation on live human embryos. They say they'll have oversight and follow federal restrictions. But the problem is, there are none. Research without restrictions? Too much room for too much abuse."
Dr. Lisa Newman, a University of Michigan professor of surgery, said in a statement released by backers of Proposal 2 that the ad "features distortions, fear-mongering and dangerous misrepresentations."
"As a doctor and an African-American, I am outraged that this ad would use a tragedy in medical history to misinform the public about health care research," Newman said.
A spokesman for the group responsible for the ad said it merely shows an example of the horrors of past unregulated scientific experimentation.
"We use an example of something that people recognize is a failure of federal oversight, of state oversight," said Dave Doyle of Michigan Citizens Against Unrestricted Science and Experimentation.
An analysis by the nonpartisan Citizens Research Council of Michigan has said research on human embryos mainly would be regulated by the federal government if Proposal 2 passes. Embryonic stem-cell research conducted with federal funding is regulated by the National Institutes of Health, according the research council's review.
Doyle contends that the proposal would keep Michigan lawmakers from regulating stem cell research, therapies or cures. He noted that not all research is funded federally.
The proposal is being fought most fiercely by Right to Life of Michigan and the Michigan Catholic Conference, which is the largest financial backer of the opposition group.
The role of endothelial-to-mesenchymal transition in cancer progression
http://www.nature.com/bjc/journal/v99/n9/full/6604662a.html
Abstract
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications
Recent evidence has demonstrated that endothelial-to-mesenchymal transition (EndMT) may have a significant role
in a number of diseases. Although EndMT has been previously studied as a critical process in heart development, it is now clear that EndMT can also occur postnatally in various pathologic settings, including cancer and cardiac fibrosis. During EndMT, resident endothelial cells delaminate from an organised cell layer and acquire a mesenchymal phenotype characterised by loss of cell–cell junctions, loss of endothelial markers, gain of mesenchymal markers, and acquisition of invasive and migratory properties.
Endothelial-to-mesenchymal transition -derived cells are believed to function as fibroblasts in damaged tissue, and may therefore have an important role in tissue remodelling and fibrosis. In tumours, EndMT is an important source of cancer-associated fibroblasts (CAFs), which are known to facilitate tumour progression in several ways. These new findings suggest that targeting EndMT may be a novel therapeutic strategy, which is broadly applicable not only to cancer but also to various other disease states.
As an integral component of the circulatory system, the endothelium can be defined as the single-cell layer of mostly squamous epithelium that provides the inner cell lining of blood vessels and lymphatics (Junqueira and Carneiro, 2005). Endothelial cells can exhibit a wide range of phenotypic variability depending on local physiologic needs throughout the vascular tree (Chi et al, 2003). Furthermore, in pathologic states, the endothelium can be affected in a number of ways; perhaps the most remarkable is an extreme form of endothelial plasticity known as endothelial-to-mesenchymal transition (EndMT).
During EndMT, resident endothelial cells delaminate from an organised cell layer and invade the underlying tissue (Figure 1). This so-called mesenchymal phenotype can be characterised by loss of cell–cell junctions, acquisition of invasive and migratory properties, loss of endothelial markers, such as CD31 (also known as platelet endothelial cell adhesion molecule-1 (PECAM-1)), and gain of mesenchymal markers, such as fibroblast-specific protein 1 (FSP1; also known as S100A4) or -smooth muscle actin (SMA; Potts and Runyan, 1989; Nakajima et al, 2000; Armstrong and Bischoff, 2004; Arciniegas et al, 2007; Zeisberg et al, 2007a, 2007b). Previous studies of EndMT have focused largely on embryonic development of the heart. However, recent evidence suggests that EndMT can occur postnatally in a variety of pathologic settings, including cancer and cardiac fibrosis (Zeisberg et al, 2007a, 2007b). There is also growing evidence that EndMT may be associated with select types of endothelium in the body.
Figure 1.Stages of EndMT. (A) Endothelial-to-mesenchymal transition may be initiated by autocrine and/or paracrine inflammatory signals originating from within the surrounding tissue, such as TGF-. Possible sources include resident fibroblasts (green) or immune cells (purple). Alternatively, the endothelium (red) may undergo EndMT in direct response to vascular injury. The vascular basement membrane is likely to be degraded by matrix metalloproteinases (MMPs) derived from local immune cells. (B–C) Transitioning endothelial cells (red/green) acquire a migratory phenotype, invade under the vascular basement membrane, and begin to express mesenchymal markers, such as FSP1, while still expressing endothelial markers. (D) Cells that have undergone EndMT (green) have lost their endothelial phenotype. These EndMT-derived cells contribute to the local fibroblast population and are likely to produce various growth factors, such as TGF-. It is not yet known whether the affected vessels are repopulated, and if they remain functional after resident endothelial cells have departed.
With regard to cancer, EndMT accounts for up to 40% of cancer-associated fibroblasts (CAFs). Cancer-associated fibroblasts play an important role in tumour progression and can alter the microenvironment in several ways. In particular, CAFs deposit various extracellular matrix molecules and secrete paracrine factors that can directly affect the behaviour of many different cell types within the tumour.
Furthermore, CAFs release potentially oncogenic signals,
such as transforming growth factor- (TGF-), and are a principle source of host-derived vascular endothelial growth factor (VEGF), which promotes angiogenesis (Kalluri and Zeisberg, 2006). Here, we highlight the recent findings of EndMT as a source of CAFs, with a discussion of proposed mechanisms and therapeutic implications.
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications.
Endothelial-to-mesenchymal transition is often categorised as a specialised form of epithelial-to-mesenchymal transition (EMT). Epithelial-to-mesenchymal transition can occur in many epithelial cell types and is a critical process in embryogenesis (Thiery and Sleeman, 2006). In the setting of disease, EMT has been demonstrated during epithelial injury and can also occur in individual tumour cells as an important mechanism of invasion and metastasis (Batlle et al, 2000; Cano et al, 2000; Zavadil and Bottinger, 2005; Thiery and Sleeman, 2006; Tse and Kalluri, 2007).
Epithelial-to-mesenchymal transition has been extensively studied and has provided a useful framework for guiding research on EndMT. Both EMT and EndMT give rise to cells that have a similar mesenchymal phenotype, and current evidence suggests that both utilise common signalling pathways. However, further studies are needed to validate this notion, as there exist some key differences between endothelial cells and other types of epithelial cells. In particular, endothelial cells express distinct cell–cell junctional proteins, different cytoskeletal proteins, different signalling machinery, and different surface markers (Table 1). The importance of these differences as they relate to EndMT needs to be fully investigated.
Table 1 - Comparison of epithelial, endothelial, and mesenchymal cells.Full table
Endothelial-to-mesenchymal transition in development
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications.
Endothelial-to-mesenchymal transition was first observed in developmental studies of heart formation (Markwald et al, 1975, 1977). In this context, a subset of endothelial cells lining the primitive heart tube are triggered to acquire a mesenchymal phenotype and invade the surrounding tissue, where they subsequently participate in forming the valves and septa of the adult heart (Armstrong and Bischoff, 2004). So far, studies of embryonic heart formation have provided the majority of current knowledge about EndMT. Mechanistic studies have demonstrated a role for TGF-, bone morphogenic protein (BMP), and Notch pathways (Potts and Runyan, 1989; Nakajima et al, 2000; Armstrong and Bischoff, 2004; Timmerman et al, 2004; Thiery and Sleeman, 2006).
Endothelial-to-mesenchymal transition in cancer and angiogenesis
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications.
Recently, studies have demonstrated that EndMT can occur in a variety of pathologic states including cancer (Zeisberg et al, 2007a) and cardiac fibrosis (Zeisberg et al, 2007b). With regard to cancer, EndMT is now recognised as a unique source of CAFs (Zeisberg et al, 2007a). Cancer-associated fibroblasts are known to facilitate tumour progression in several ways (reviewed by Kalluri and Zeisberg, 2006), and are a key component of tumour stroma. The discovery of EndMT in tumours was reported in a recent study that investigated two different mouse models of cancer and demonstrated that a substantial proportion of CAFs arise through EndMT. These CAFs were identified as a unique population of cells that coexpress the endothelial marker CD31 along with one of the mesenchymal markers, FSP1, or SMA. Approximately, 40% of FSP1+ CAFs were also found to be CD31+, as were 11% of SMA+ CAFs.
Furthermore, this study also investigated tumours grown in Tie2-Cre;R26R-lox-STOP-lox-lacZ transgenic mice, a reporter strain that allows all cells of endothelial origin to be irreversibly labelled with lacZ expression (Figure 2A). Similar results were found: among FSP1+ CAFs, 30% were also lacZ+, and among SMA+ CAFs, 12% were lacZ+. These data suggest that EndMT is an important mechanism for CAF recruitment to the tumour stroma and that these CAFs may have a unique role in tumour progression. Coincidentally, TGF- signalling is a known mediator of EndMT (Nakajima et al, 2000) and is abundantly expressed in many different tumours (Zeisberg et al, 2007a), therefore suggesting that EndMT may be mediated by TGF- signalling in this context. Nevertheless, the molecular mechanism of EndMT in tumours has not yet been specifically studied, but is likely to involve similar pathways as described in the setting of cardiac fibrosis (Figure 2B).
Figure 2.Endothelial-to-mesenchymal transition in cancer and cardiac fibrosis.
(A) The Tie2-Cre;ROSA-STOP-lacZ reporter mouse is an important strain for tracking cells of endothelial origin during EndMT. In this mouse, Cre expression is driven by the Tie2 promoter, which is known to be active in endothelial cells.
The Cre recombinase acts by permanently excising genomic DNA regions that are flanked by loxP sites (floxed). In this case, Tie2-driven Cre activity removes a floxed stop cassette, thereby allowing lacZ expression to be driven by the constitutive ROSA26R promoter (ROSA) without the need for continued Tie2 activity. (B) During cardiac fibrosis, TGF- signalling promotes EndMT through Smad3 transcriptional activity. In endothelial cells, TGF- is known to activate Alk5, which then activates Smad3. However, the role of Alk5 has not been explicitly demonstrated during EndMT in cardiac fibrosis. EndMT was also shown to be inhibited by rhBMP-7 (dashed lines). BMP-7 is known to act through a different set of Smads, namely Smad1, -5, and -8. However, the precise mechanisms whereby BMP-7 inhibits EndMT are not yet known.
Taken together, these results demonstrated that up to 40% of CAFs might be derived through EndMT. This study has furthermore demonstrated that angiogenic vessels can undergo EndMT. We speculate that EndMT may play a role in angiogenic sprouting by enabling the so-called tip cells, which lead an emerging vascular plexus, to migrate into adjacent tissue.
As migratory cells with no lumen (Gerhardt et al, 2003), tip cells have a phenotype that appears to be consistent with EndMT. At the angiogenic front, these migrating endothelial cells are exposed to growth factors and interstitial matrix molecules, such as type I collagen, which differ from their normal vascular basement membrane components (Davis and Senger, 2005). Perhaps in response to these factors, some endothelial cells may undergo EndMT and maintain their mesenchymal phenotype indefinitely. Moreover, previous reports have suggested that vascular support cells, such as pericytes and/or smooth muscle cells, may arise from the endothelium itself, and therefore EndMT may be an important mechanism in recruiting such mural cells during angiogenesis (Armulik et al, 2005). Furthermore, these vascular support cells are an important component of mature vessels (Armulik et al, 2005), and therefore EndMT may play an important role in stabilizing the neovasculature during vasculogenesis and angiogenesis. This would be consistent with the finding that a subpopulation of EndMT-derived cells express SMA, a well-established marker for pericytes and vascular smooth muscle cells (Armulik et al, 2005).
Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications
Another recent study has further validated the notion that EndMT can occur postnatally in the context of disease.
This study addressed EndMT during cardiac fibrosis, a common feature of most forms of heart failure (Zeisberg et al, 2007b). In fact, postnatal EndMT has been most extensively studied in this setting of cardiac fibrosis. Here, approximately 27–35% of all fibroblasts in fibrotic heart tissue were found to arise through EndMT. Furthermore, this study demonstrated a role for Smad3-dependent TGF- signalling during EndMT in vivo (Figure 2B). Interestingly, mice treated with recombinant human BMP-7 (rhBMP-7, another member of the TGF- superfamily known to antagonise the effects of TGF-) exhibited a significant reduction both in fibrosis as well as EndMT (Figure 2B).
In addition to the studies described above, there is evidence to suggest that EndMT may occur in many other disease settings, such as chronic pulmonary hypertension (Zhu et al, 2006; Arciniegas et al, 2007), atherosclerosis (Mironov et al, 1995), wound healing (Sarkisov et al, 1988; Lee and Kay, 2006), and in both acute and chronic kidney injury (Zeisberg et al, 2008). These emerging reports have characterised EndMT primarily in terms of marker expression, but have not addressed the precise molecular mechanisms of EndMT in disease. More importantly, the functional role of EndMT in each of these scenarios has not yet been determined.
Signalling during EndMT
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications.
In addition to the in vivo studies described above, a number of reports have also demonstrated the induction of EndMT in vitro. To date, many different endothelial cell types, including both human and mouse, have demonstrated EndMT when exposed to TGF- or Notch ligands in vitro (Frid et al, 2002; Ishisaki et al, 2003; Noseda et al, 2004; Timmerman et al, 2004; Zeisberg et al, 2007a, 2007b). These studies have led to a greater understanding of the mechanisms driving EndMT. In vivo studies have further substantiated that EndMT can be modulated in response to manipulations of the TGF- or Notch pathways (Sanford et al, 1997; Timmerman et al, 2004; Zeisberg et al, 2007b). Still, it is not clear whether Notch, TGF-, or a combination of both pathways provides the initiating signal under physiologic conditions in vivo. It is also likely that other signalling pathways interact with TGF- and Notch to mediate EndMT. For example, VEGF, NFAT, BMP, Wnt/-catenin, ErbB, and NF1/Ras have been implicated in EndMT during cardiac development (Armstrong and Bischoff, 2004), but have yet to be specifically explored in the context of pathology. In fact, the majority of mechanistic work related to EndMT has been performed in the context of embryonic development, and therefore may not reflect the same mechanisms that occur in disease.
Downstream of these signalling events, the transcriptional networks mediating EndMT also remain largely unidentified.
In one series of experiments, cells that undergo EndMT exhibited an increased expression of the Snail family of transcriptional repressors (Carmona et al, 2000; Romano and Runyan, 2000; Timmerman et al, 2004). Snail proteins are also known to be upregulated during EMT, where they play a critical role in disrupting cell–cell junctions (Batlle et al, 2000; Cano et al, 2000; Nieto, 2002). In the context of EndMT, Snail repressors are believed to downregulate VE-cadherin, thereby disrupting adherens junctions and allowing endothelial cells to delaminate and undergo EndMT. It is unknown whether other effectors of EMT, such as Twist (Thiery and Sleeman, 2006), CArG box-binding factor A (CBF-A), and KRAB-associated protein 1 (KAP-1) (Venkov et al, 2007), are also involved in EndMT.
Perspectives and therapeutic implications
Endothelial-to-mesenchymal transition vs epithelial-to-mesenchymal transition Endothelial-to-mesenchymal transition in development Endothelial-to-mesenchymal transition in cancer and angiogenesis Endothelial-to-mesenchymal transition in cardiac fibrosis and other diseases Signalling during EndMT Perspectives and therapeutic implications.
Studies of EndMT have revealed a novel mechanism of fibroblast and mural cell recruitment that is likely to be involved in many different disease settings. Fibroblasts are known to have an important role in tissue remodelling and fibrosis (Tomasek et al, 2002; Kalluri and Zeisberg, 2006; Zeisberg et al, 2007a, 2007b), although previously very little was known about the origin of fibroblasts in damaged tissues.
Various mechanisms have been proposed, including the activation of local fibroblasts within the affected tissue, recruitment of bone marrow-derived precursors, and EMT occurring in nearby epithelia (Iwano et al, 2002). However, in addition to these mechanisms, it is now clear that EndMT accounts for a considerable proportion of these fibroblasts, estimated at 27–35% during cardiac fibrosis and up to 40% in tumours (Zeisberg et al, 2007a, 2007b). This suggests that fibroblasts can be recruited from a combination of sources, although the relative contribution from each source may vary in different disease states. It is also possible that certain vascular beds are more likely to be affected by EndMT. The endothelium is highly heterogenous and dynamic by nature, and therefore future studies will need to address EndMT in the context of this inherent variation in endothelial phenotypes. For instance, angiogenic vessels in tumours seem to be particularly prone to EndMT.
Perhaps most importantly, the recent discoveries of EndMT in different diseases suggest that modulating EndMT may represent a promising new treatment modality. The endothelium itself is an attractive target for drug delivery because it lies in direct contact with the bloodstream. We hypothesise that therapies directed at inhibiting EndMT may delay tumour progression, perhaps as a result of impaired angiogenesis or CAF recruitment. Possible treatment strategies may target the TGF- and/or BMP signalling pathways.
The mouse studies described above have demonstrated that systemic administration of rhBMP-7 significantly reduced EndMT during cardiac fibrosis (Zeisberg et al, 2007b). Follow-up studies should be pursued to address possible effects of BMP-7 treatment on EndMT in tumours and to identify other EndMT targets.
Furthermore, inhibiting EndMT may be broadly applicable to various disease states. For example, preventing EndMT during chronic organ fibrosis may significantly delay disease progression and allow patients to maintain adequate organ function for a longer period of time. Nevertheless, additional studies are needed to identify the precise molecular mechanisms of EndMT in disease and to determine which signalling components might be viable therapeutic targets. A promising place to start may be to further examine the developmental defects in EndMT. Just as normal developmental mechanisms are often recapitulated in certain disease states (Reya et al, 2001), the corresponding developmental defects might provide unique insights into possible treatments for those diseases.
In conclusion, the study of EndMT represents an exciting new frontier in vascular biology that will continue to provide novel insights into the mechanisms of human disease.
S Potenta1,2, E Zeisberg1 and R Kalluri1,3,4
1Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
2Department of Cell Biology, Harvard Medical School, Boston, MA, USA
3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
4Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
Correspondence: Dr R Kalluri, E-mail: rkalluri@bidmc.harvard.edu
Received 27 May 2008; Accepted 18 August 2008; Published online 16 September 2008.
Mechanism In Cells That Generate Malignant Brain Tumors May Offer Target For Gene Therapy
http://www.sciencedaily.com/releases/2008/10/081024103221.htm
(Oct. 26, 2008) — Researchers at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute who first isolated cancer stem cells in adult brain tumors in 2004 have now identified a molecular mechanism that is involved in the development of these cells from which malignant brain tumors may originate. This could offer a target for scientists seeking treatments that would kill malignant brain tumors at their source and prevent them from recurring.
Normal stem cells are "immature" cells that have the potential to become any of several types of cells.
Cancer stem cells have the same multi-potent and self-renewing properties, but instead of producing healthy cells, they propagate cancer cells. Theoretically, if these "mother cells" can be destroyed, the tumor will not be able to sustain itself. On the other hand, if these cells are not removed or destroyed, the tumor will continue to return despite the use of existing cancer-killing therapies.
Glioblastoma multiforme is the most malignant form of tumor that develops in the brain, but not all glioblastomas are identical. Subgroups are comprised of cells originating from different brain tumor stem cells with unique genetic characteristics that use different signaling pathways in their development and growth. The Cedars-Sinai researchers are building genetic "profiles" of these cancer stem cells and the tumors they appear to produce.
In this study, published in the journal Stem Cells (Stem Cells Express online Sept 11., ahead of print), the researchers identified a subset of brain tumor stem cells that is dependent on a protein called Sonic Hedgehog and another subset that is not Hedgehog dependent. The brain tumors resulting from each subset retained the "signaling dependency" characteristics of the mother cells, and in laboratory experiments and studies in laboratory mice, pathway-specific blocking interventions prevented the brain tumor stem cells from being able to renew themselves.
Although cancer stem cell involvement in the genesis of brain tumors is hypothetical and in the early stages of scientific discovery, the Sonic Hedgehog signaling mechanism appears to be one of the molecular mechanisms regulating both normal stem cell growth and cancer stem cell growth.
"According to our analysis, patients who have malignant brain tumors produced from cancer stem cells that rely on this mechanism have a shorter survival than those who don't," said John S. Yu, M.D., director of Surgical Neuro-oncology at Cedars-Sinai and senior author of the Stem Cells article.
Further investigation of these and other pathways may allow scientists to devise therapies to block the underlying cancer-causing mechanisms with genes or small molecules, according to the research team.
"Understanding the mechanisms behind cancer stem cells, which may be the root and cause of cancers, may allow us to determine how these cancers start and, more importantly, how best to target them to prevent their growth and spread," said Keith L. Black, M.D., chairman of the Department of Neurosurgery, director of the Maxine Dunitz Neurosurgical Institute, and one of the paper's authors.
After isolating cancer stem cells in adult brain tumors in 2004, the Cedars-Sinai researchers in 2006 reported that these cells are highly resistant to chemotherapy and other treatments. Even if a tumor is almost completely obliterated, it will regenerate from the surviving cancer stem cells and be even more resistant to treatment than before.
This study was supported in part by grants from the National Institutes of Health.
Journal reference:
. Hedgehog signaling regulates brain tumor stem cell self-renewal and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells, Sept. 11, 2008
Adapted from materials provided by Cedars-Sinai Medical Center.
Good morning Preciouslife 1
I see you like the Stem cells as well as Baseball!
Here's a news article relative to stem cell research and the 2008 election, either way, stems should move up, finally.
Whatever side you are on, the advancement of this research is critical for everyone, young and old. Again jmho. Long article, my apologies.
Obama's Stem Cell Spinning
September 30, 2008
His radio ad is wrong: McCain still supports federal funding for stem cell research.
Summary
An Obama-Biden radio ad hammers McCain for being opposed to stem cell research. Not true. Meanwhile two spots from the McCain-Palin campaign, together with the Republican National Committee, describe McCain's support for the research; they're largely accurate.
By saying that "John McCain has stood in the way – he's opposed stem cell research," the Obama ad seriously misstates the view that McCain has held on this issue since 2001, when he began backing embryonic stem cell research, a position that was out of step with that of many of his fellow Republicans.
The McCain/RNC ads would probably lead listeners to believe that Palin shares McCain's views on this topic. That's not true. But we find that to be a minor flaw compared with the misrepresentation in Obama's ad.
Analysis
We first noticed that stem cell research had become a subject of campaign radio ads when Sen. John McCain and the Republican National Committee released one on Sept. 12 touting his support for it. Then Sen. Barack Obama came back with his own ad, saying that "John McCain has stood in the way – he's opposed stem cell research." McCain and the RNC countered with yet another, this time taking the Obama campaign to task for its ad.
Republican National Committee Ad:
"Stem Cell"
Announcer: They're the original mavericks. Leaders. Reformers. Fighting for real change.
John McCain will lead his congressional allies to improve America's health.
Stem cell research to unlock the mystery of cancer, diabetes, heart disease. Stem cell research to help free families from the fear and devastation of illness. Stem cell research to help doctors repair spinal cord damage, knee injuries, serious burns. Stem cell research to help stroke victims.
And, John McCain and his congressional allies will invest millions more in new NIH medical research to prevent disease. Medical breakthroughs to help you get better, faster.
Change is coming. McCain-Palin and congressional allies. The leadership and experience to really change Washington and improve your health.
Paid for by McCain-Palin 2008 and the Republican National Committee.
McCain: I'm John McCain and I approve this message.What'd We Miss?
McCain has been known for supporting federally funded stem cell research since 2001, so his first ad didn't ring any alarm bells with us. It touted McCain's support for "stem cell research to unlock the mystery of cancer, diabetes, heart disease."
Obama's ad did set sirens off, however. McCain "stood in the way" and "opposed stem cell research"? Maybe we'd missed something.
McCain didn't mention embryonic stem cell research in his ad, a subject that has put him at odds with some in his party, including President George W. Bush (though, notably, not former First Lady Nancy Reagan, whom he credited with helping to change his stance back in '01). Was he now in favor of using only adult stem cell lines for research, and had he done something to "stand in the way" of other options?
Nope. It turns out nothing much has changed at all. In 2004, McCain was one of 14 GOP members of Congress who signed a letter to Bush asking him to lift restrictions on federal funding for embryonic stem cell research, citing its potential to lead to treatments or cures for deadly and crippling diseases and conditions. In 2006, he was one of 19 Republicans to vote for federal funding for embryonic stem cell research, a bill that Bush vetoed. The bill allowed use only of embryos that were frozen or slated for destruction anyway by fertility clinics. There was a similar vote in 2007, in which McCain voted the same way.
McCain's response to a question about funding embryonic stem cell research at an MSNBC Republican candidate debate in 2007 was strongly supportive.
Q: Would you expand federal funding of embryonic stem cell research?
McCain (May 3, 2007): I believe that we need to fund this. This is a tough issue for those of us in the pro-life community. I would remind you that these stem cells are either going to be discarded or perpetually frozen. We need to do what we can to relieve human suffering. It's a tough issue. I support federal funding.
And now? The McCain-Palin campaign's Web site says the ticket supports embryonic stem cell research, but not the creation of embryos for that purpose, which is right in line with previous statements he's made:
Obama-Biden Ad:
"Stem Cell"
Obama: I'm Barack Obama, candidate for president, and I approve this message.
Jody Montgomery: My name is Jody Montgomery and my daughter Maddy was diagnosed with Type I Juvenile Diabetes at age three. Six times a day, I take her blood. Six times a day, I pray for a cure. Researchers are working hard to do just that. Our best hope is stem cell research, and that's why we support Barack Obama.
Announcer: Stem cell research could unlock cures for diabetes, cancer and Alzheimer's too. But John McCain has stood in the way – he's opposed stem cell research. Picked a running mate who's against it. And he's running on a platform even more extreme than George Bush's on this vital research. John McCain doesn't understand that medical research benefiting millions shouldn't be held hostage by the political views of a few.
Montgomery: For Maddy and millions of others, stem cell research can unlock cures. Barack Obama understands that. But John McCain just doesn't.
Announcer: Paid for by Obama for America McCain-Palin site: John McCain opposes the intentional creation of human embryos for research purposes. To that end, Senator McCain voted to ban the practice of "fetal farming," making it a federal crime for researchers to use cells or fetal tissue from an embryo created for research purposes.
McCain elaborated in an answer he gave Science Debate 2008, a group whose members include numerous Nobel laureates, elected officials, university presidents and others, when it asked him for his position on "government regulation and funding of stem cell research":
McCain (Sept. 15): While I support federal funding for embryonic stem cell research, I believe clear lines should be drawn that reflect a refusal to sacrifice moral values and ethical principles for the sake of scientific progress. Moreover, I believe that recent scientific breakthroughs raise the hope that one day this debate will be rendered academic. I oppose the intentional creation of human embryos for research purposes and I voted to ban the practice of “fetal farming,” making it a federal crime for researchers to use cells or fetal tissue from an embryo created for research purposes.
Will It Cure Lame Back-Up Disease?
To substantiate its claim that McCain "opposed" and "stood in the way" of stem cell research, the Obama-Biden campaign offers support that can charitably be described as inadequate. The campaign cites an article that describes McCain's meeting with a group of Christian conservative leaders. The article quotes some participants as saying "they were impressed that he seemed open" to the points made by one of the nation's leading opponents of embryonic stem cell research. But the article also said McCain "did not offer any indication he would change his mind."
The Obama camp also cites two articles saying that religious conservatives weren't enthusiastic about McCain in part because of his position on the issue, and another describing Republican Rep. Mike Castle's concern that McCain could flip due to pressure from the evangelical wing of the party. Castle is a strong proponent of federal backing of embryonic stem cell research.
We'd say that the Obama campaign's arguments add up to pretty weak tea, but that would be a slight to the popular and storied beverage.
McCain-Palin/ Republican National
Committee Ad:
"Stem Cell Response"
Announcer: Barack Obama and his congressional allies’ stem cell attacks are simply not true. Leading news organizations call their attacks “misleading.” “Out of bounds.” “Manhandling the truth.” “Wrong.”
The truth? John McCain and his congressional allies fought FOR stem cell research. They stood up and said stem cell research was too important for you and your family.
Stem cell research will help unlock the mystery of cancer, diabetes and heart disease. It will allow scientists to explore treatment for Parkinson’s and Alzheimer’s. Stem cell research will help free families from the fear and devastation of illness.
Change is coming. McCain-Palin and congressional allies. The leadership and experience to change Washington and improve your health.
Paid for by McCain-Palin 2008 and the Republican National Committee.
McCain: I'm John McCain and I approve this message.A Little Off
As for the McCain/RNC ads, their main flaw is in implying that running mate Sarah Palin's position is in line with McCain's.
The "original mavericks??" "Fighting for real change?" In Palin's case, the language doesn't apply, not on this topic. Palin opposes stem cell research. (On this point, the Obama ad is correct.) In a 2006 gubernatorial debate in Alaska, she said:
Palin (Nov. 2, 2006): ts interesting that so many questions revolve around this centeredness I have for respecting life, and the potential of every human life, but no, stem-cell research would ultimately end in the destruction of life. I couldn’t support it.
Palin's response to ABC News' Charlie Gibson, in her first post-convention major media interview, was similar:
Gibson (Sept. 12): Embryonic stem cell research, John McCain has been supportive of it.
Palin: My personal opinion is we should not create human life, create an embryo and then destroy it for research, if there are other options out there. And thankfully, again, not only are there other options, but we're getting closer and closer to finding a tremendous amount more of options, like, as I mentioned, the adult stem cell research.
But Palin has acknowledged more than once (including in the Gibson interview) that McCain's ideas would prevail if the ticket is elected Nov. 4. And McCain hasn't adjusted the stem cell language on his campaign Web site since Palin came on board.
It's also true that the Republican platform calls for a ban on any research experimentation on human embryos, regardless of whether the embryos were scheduled for destruction or not:
Republican Platform, 2008: We call for a ban on human cloning and for a ban on the creation of or experimentation on human embryos for research purposes.
Despite all the sturm-und-drang that goes into cobbling together a party platform, the truth is that it doesn't dictate a candidate's positions or how he will govern if elected.
In this set of ads, the misimpressions created by the Obama-Biden ad are far worse than the passing blip in the McCain-Palin/RNC spots. The Democrats' ad should be shelved in a closet and hauled out only if McCain really does change his position on stem cell funding. So far, that's not the case.
–by Viveca Novak
Sources
California Republican Debate Transcript, MSNBC, 3 May 2007.
Addressing the Moral Concerns of Advanced Technology, McCain-Palin 2008 Web site, accessed 29 September 2008.
McCain Statement on Stem Cell Research, United States Senate Web site of Sen. John McCain, 18 July 2006.
John McCain's answers to the top 14 science questions facing America, Science Debate 2008 Web site, 15 Sept. 2008.
Copyright © 2003 - 2008, Annenberg Public Policy Center of the University of Pennsylvania
FactCheck.org's staff, not the Annenberg Center, is responsible for this material.
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Prostates Grown from Stem Cells
http://www.technologyreview.com/biomedicine/21594/
New proof that the mouse prostate contains stem cells could aid cancer research.
By Jocelyn Rice Thursday, October 23, 2008
A single adult stem cell from the prostate of a mouse can develop into an entire functional organ, scientists reported online yesterday in Nature. The finding proves that a population of stem cells exists in the adult prostate, as many have long suspected, and it could provide insight into how prostate cancer develops.
"It's extremely exciting, the concept that you can reconstitute an entire prostate from a single cell," says Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research, at MIT, who was not involved in the work. "That's impressive stuff."
Unlike embryonic stem cells, which can potentially develop into any cell type in the body, adult stem cells are tissue-specific. Many organs are believed to house populations of adult stem cells, but in most cases their existence remains unproven. Known adult stem cells, however, can give rise to all the cell types that characterize the organs in which they're found.
To sift out potential adult prostate stem cells, researchers at Genentech, in San Francisco, zeroed in on a group of cell-surface markers associated with suspected prostate stem cells. Since many of these markers are individually unreliable and poorly understood, the researchers tested a new one as well: a receptor protein called c-kit, which is known to be associated with other types of stem cells.
Using c-kit and three other markers, the researchers, led by senior scientist Wei-Qiang Gao, isolated a small population of likely stem cells from the prostates of mice. But while markers can point to candidates, they can't unequivocally prove the identity of a stem cell. The cell still needs to demonstrate the capacity to develop into an entire organ.
To test for that capacity, Gao and his colleagues grafted individual stem-cell candidates onto the kidneys of living mice. In order to provide necessary developmental cues, they transferred, along with each cell, some connective cells from the urogenital cavities of rats. Three months later, the researchers removed the kidneys and analyzed the fate of the grafted cells. Of the 97 single-cell transplants, 14 had grown into fully functioning prostates--complete with multiple cell types, characteristic branching structures, and prostate-specific proteins.
Other groups have grown prostates in living mice from clumps of cells, but never before from a single cell. "That's really the gold standard--that there's an adult, tissue-specific stem cell," says Scott Cramer, an associate professor of cancer biology at Wake Forest University School of Medicine, who was not involved in the study. The only other solid tissue for which this feat has been accomplished is the breast: a single breast stem cell can develop into an entire mammary gland.
Adult stem cells have been touted for their promise in regenerative medicine. But there is no clinical reason to regrow a prostate, says Leisa Johnson, a senior scientist at Genentech and coauthor of the Nature paper. The vast majority of prostate-cancer patients are beyond their child-bearing years, and the main side effects of prostate removal--urinary incontinence and impotence--are caused by nerve disruption during surgery, so they wouldn't be remedied by a new prostate.
Even so, says Jacks, the newly isolated prostate stem cells may provide insight into adult stem cells in general. "Our understanding of stem cells--and adult stem cells in particular--might allow us to re-create damaged tissues that are lost during debilitating diseases," he says.
More important, however, the stem cells may have much to reveal about prostate cancer. Only a small number of cells in a tumor actually have the capacity to spawn an entire tumor, with all its various cell types. Many researchers speculate that these cells, dubbed cancer stem cells or cancer-initiating cells, have much in common with normal adult stem cells. Some even suspect that cancer stem cells and normal stem cells are one and the same.
"We now believe that for many types of cancer, the cell that gives rise to the cancer in the normal tissue is itself a stem cell," says Jacks. "If that is true for prostate cancer, then having the ability to purify and therefore study the normal stem cell would be an important tool in understanding how prostate cancer originates."
Johnson agrees. "By gaining insights into the normal stem cell of the prostate, our hope is to gain better understanding of the cancer-initiating cell," she says.
If it does turn out that stem cells, or stemlike cells, are responsible for triggering prostate cancer, markers like c-kit may also point the way to potential treatments. Now that the Genentech researchers have a pool of definitive prostate stem cells on hand, they can revise the catalogue of known prostate stem-cell markers and even begin to define their function. If any markers turn out to be essential for stem-cell proliferation, they would be ideal drug targets.
Characterizing the newly discovered prostate stem cells may also produce better ways to detect prostate cancer. "These cells could easily turn out to be the cells of origin for prostate cancer," says Jacks, "and if you're interested in early detection, it is important to understand where these cancers come from."
Stem cell trial nearly a go?
http://www.the-scientist.com/blog/display/55096/
Posted by Andrea Gawrylewski
The first clinical trial treatment based on embryonic stem cells may soon get the go ahead.
In May, the Food and Drug Administration placed a hold on a clinical trial application submitted by Geron Corporation, a California-based biotech. The company submitted a 22,500-page Investigational New Drug application to the FDA for an embryonic stem cell-derived compound -- called GRNOPC1 -- to treat spinal cord injury.
Geron president and CEO, Tom Okarma, said at the New York Stem Cell Foundation conference at Rockefeller University on Wednesday (October 15) that the company has had to "educate" the FDA on all the procedures used to grow, quantify, and characterize their stem cell populations. He added that there is no evidence of political pressures behind the hold, and he thinks the FDA did the right thing to hold the trial, in order to get a grasp on the science and ensure safety.
But the FDA is nearing the end of its review process and may lift the hold and allow clinical trials to commence within the next three months, Okarma told The Scientist. "We've got our arms wrapped around it," he added. "It's been a long education process."
Stem Cell Breakthrough: Mass-Production Of 'Embryonic' Stem Cells From A Human Hair
http://www.sciencedaily.com/releases/2008/10/081017164917.htm
(Oct. 18, 2008) — The first reports of the successful reprogramming of adult human cells back into so-called induced pluripotent stem (iPS) cells, which by all appearances looked and acted like embryonic stem cells, created a media stir.
But the process was woefully inefficient: Only one out of 10,000 cells could be persuaded to turn back the clock.
Now, a team of researchers led by Juan Carlos Izpisúa Belmonte at the Salk Institute for Biological Studies, succeeded in boosting the reprogramming efficiency more than 100-fold, while cutting the time it takes in half. In fact, they repeatedly generated iPS cells from the tiny number of keratinocytes attached to a single hair plucked from a human scalp.
Their method, published ahead of print in the Oct. 17, 2008 online edition of Nature Biotechnology, not only provides a practical and simple alternative for the generation of patient- and disease-specific stem cells, which had been hampered by the low efficiency of the reprogramming process, but also spares patients invasive procedures to collect suitable starting material, since the process only requires a single human hair.
"Having a very efficient and practical way of generating patient-specific stem cells, which unlike human embryonic stem cells, wouldn't be rejected by the patient's immune system after transplantation brings us a step closer to the clinical application of stem cell therapy," says Belmonte, PhD., a professor in the Gene Expression Laboratory and director of the Center of Regenerative Medicine in Barcelona, Spain.
Keratinocytes form the uppermost layer of skin and produce keratin, a tough protein that is the primary constituent of hair, nails and skin. They originate in the basal layer of the epidermis, from where they move up through the different layers of the epidermis and are eventually shed.
While scientists have successfully reprogrammed different types of mouse cells (fibroblasts, liver and intestinal cells), skin fibroblasts were the only human cell type they had ever tried their hands on. Fibroblasts help make the connective tissue in the body and are the primary cell type in the deeper layers of the skin, where they are responsible for wound healing and the secretion of proteins that form collagen.
For the first set of experiments, first author Trond Aasen, Ph.D., a postdoctoral researcher at the Center of Regenerative Medicine in Barcelona, used viral vectors to slip the genes for the master regulators Oct4, Sox2, as well as Klf4 and c-Myc into keratinocytes cultured from human skin explants. After only 10 days — instead of the more typical three to four weeks — one out of 100 hundred cells grew into a tiny colony with all the markings of a typical human embryonic stem cell colony.
The researchers then successfully prodded what they call keratinocyte-derived iPS cells or KiPS cells to distinguish them from fibroblast-derived iPS cells into becoming all the cell types in the human body, including heart muscle cells and dopamine-producing neurons, which are affected by Parkinson's disease.
Taking advantage of the high efficiency of the keratinocyte reprogramming process, Aasen decided to test whether he could establish KiPS cells from minute amounts of biological samples. "We plucked a single hair from a co-worker's scalp and cultured the keratinocytes, which are found in the outer root sheet area," recalls Aasen. He then successfully reprogrammed these cells into bona fide KiPS cells.
Just why keratinocytes appear to be much more malleable than other cell types is still an open question. "We checked a whole rainbow of cells and found keratinocytes to be the easiest to be reprogrammed," says Belmonte. "It is still not clear exactly why that is and knowing it will be very important for the technology to develop fully," he speculates.
They researchers did find one hint, though. When they compared the expression profiles of genes related to stem cell identity, growth or differentiation between keratinocytes, fibroblasts, human embryonic stem cells (hESC) and KiPS cells, keratinocytes had more in common with hESCs and KiPS cells than with fibroblasts.
Researchers who also contributed to the study include Angel Raya, Ph.D., Maria J. Barrero, Ph.D., Elena Garreta, Ph.D., Antonella Consiglio, Ph.D., Federico Gonzales, Ph.D., Rita Vassena, Ph.D., Josipa Bilic, Ph.D., Vladimir Pekarik, Ph.D., Gustavo Tiscornia, Ph.D., Michael Edel, Ph.D., and Stéphanie Boué, Ph.D., at the Center of Regenerative Medicine in Barcelona, Spain.
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This board is created for the discussion of any stem cell stock since the 'stem' sector is heating
up again, finally; for example: astm, stem, gern , ccel.ob, plrs.ob and others feel free to add
& join in the on-topic discussion.
Stocks:
Aastrom (ASTM):
http://finance.yahoo.com/q/ks?s=ASTM
http://finance.yahoo.com/q/pr?s=astm
http://www.investorshub.com/boards/board.asp?board_id=2080
Stem Cells (STEM):
http://finance.yahoo.com/q/ks?s=STEM
http://finance.yahoo.com/q/pr?s=STEM
http://www.investorshub.com/boards/board.asp?board_id=3023
Geron Corporation (GERN)
http://finance.yahoo.com/q/ks?s=gern
http://finance.yahoo.com/q/pr?s=gern
http://www.investorshub.com/boards/board.asp?board_id=1634
Advanced Cell Technology Inc. (ACTC.OB)
http://finance.yahoo.com/q?s=ACTC.OB
http://www.investorshub.com/boards/board.asp?board_id=5319
TISSERA INC (TSSR.OB):
http://finance.yahoo.com/q?s=TSSR.OB
http://finance.yahoo.com/q/h?s=TSSR.OB
Contact:
Tissera, Inc.
(Investor Relations)
Dr. Uri Elmaleh, 972-9-9561151
uri@tissera.com
Source: Tissera, Inc.
BioStem Inc.(BTEM.OB):
http://finance.yahoo.com/q/pr?s=BTEM.OB
http://finance.yahoo.com/q/ks?s=BTEM.OB
http://www.investorshub.com/boards/board.asp?board_id=7996
Stem Cell Innovations:
http://www.investorshub.com/boards/board.asp?board_id=5472
OSIR ~ Osiris Therapeutics (NasdaqGM:OSIR)
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=33470989
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=33471053
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Stem Cell Storage Stocks
Cryo-Cell International Inc. (CCEL.OB)
ccel>>http://finance.yahoo.com/q/ks?s=ccel.ob
http://finance.yahoo.com/q/pr?s=ccel.ob
http://www.investorshub.com/boards/board.asp?board_id=3965
Cord Blood America Inc. (CBAI.OB)
http://www.cordblood-america.com/
http://finance.yahoo.com/q?s=cbai.ob&d=t
http://finance.yahoo.com/q/pr?s=CBAI.OB
http://www.smallcapwatch.com/company.asp?TICKER=cbai
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Thermogenics board: KOOL
http://investorshub.advfn.com/boards/board.aspx?board_id=13388
RESEARCH ARTICLES:
http://news.google.com/news?q=Stem+cell+news&hl=en&um=1&sa=X&oi=news_group&resnum=4&ct=title
http://www.stemcellresearchnews.com/
http://science.bio.org/cloning.news.html
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Charts:
galleryview/stockcharts,http://stockcharts.com/charts/candleglance.php?STEM,KOOL,ASTM,ALNY,CLBE,CBAI,GERN,PSTI|B|L....
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Helpful Links:
http://www.nature.com/stemcells/index.html
http://www.stemcellresearchnews.com/stem_cell_lab__world.htm
http://www.nature.com/stemcells/index.html
http://stemcells.nih.gov/policy/legislation.asp
http://www.stemcellnews.com/
http://www.stemcell.com/
http://www.scirus.com/srsapp/search?
http://www.stemcellresearchnews.com/
Sticky Post: For news in the Stem Cell sector:
http://www.stemcellresearchnews.com/
http://www.stemcellnews.com/
http://www.sciencedaily.com/news/health_medicine/stem_cells/
PL1
http://stemcells.nih.gov/policy/taskForce/workingGroups/resourceaccess/raMembers.asp
http://novocell.com/
Medical World News:
http://investorshub.advfn.com/boards/board.asp?board_id=10777
Thank you for visiting the StemWare board here on IHUB, and please feel free to post information on Stem Cell stocks and Stem Cell news.....PL1
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