Sub-Areas to Progenitors:
Derived from Adult Islet Cells
(2)
Pancreatic Epithelial Cells
(7)
Differentiation
(1)
Transdifferentiation
(2)
Insulinotropic Substances
(1)
(Journal Article): Insulin-Producing Cells from Tissue Stem/Progenitor Cells: Are Autologous Cells Preferable to Allogeneic?
Efrat S (Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978 Israel,
sefrat(at)post.tau.ac.il
)
IN:
Rev Diabetic Stud
2005; 2(1):3-8
Impact Factor(s) of Rev Diabetic Stud: 0.125 (2006)
ABSTRACT: Type 1 diabetes is caused by autoimmune destruction of the pancreatic islet insulin-producing β-cells. Insulin administration does not prevent long-term complications of the disease, since the optimal insulin dosage is difficult to adjust. Replacement of the damaged cells with regulated insulin-producing cells is considered as the ultimate cure for type 1 diabetes. Transplantation of intact human pancreas or isolated islets has been severely limited by the scarcity of human tissue donors, and the search is on for an abundant source of human insulin-producing cells. Isolated human islets have been difficult to expand in tissue culture without partial or complete loss of function. Recent progress in stem cell biology has fanned hopes for the generation of regulated insulin-producing cells by differentiation from various sources of stem/progenitor cells.
TYPE OF PUBLICATION: Editorial
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(Journal Article): Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets
Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4092, USA)
IN:
Science
2001; 292:1389-1394
Impact Factor(s) of Science: 30.927 (2005), 31.853 (2004), 29.162 (2003), 26.682 (2002), 23.329 (2001)
ABSTRACT: Although the source of embryonic stem (ES) cells presents ethical concerns, their use may lead to many clinical benefits if differentiated cell types can be derived from them and used to assemble functional organs. In pancreas, insulin is produced and secreted by specialized structures, islets of Langerhans. Diabetes, which affects 16 million people in the United States, results from abnormal function of pancreatic islets. We have generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells. The cells self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons. Glucose triggers insulin release from these cell clusters by mechanisms similar to those employed in vivo. When injected into diabetic mice, the insulin-producing cells undergo rapid vascularization and maintain a clustered, islet-like organization.
TYPE OF PUBLICATION: Original article
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(Journal Article): Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells.
Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK (Department of Developmental Biology and Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA)
IN:
Proc Natl Acad Sci USA
2002; 99:16105-16110
ABSTRACT: The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic beta cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.
TYPE OF PUBLICATION: Original article
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(Journal Article): Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells.
Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM (In Vitro Differentiation Group, Institute of Plant Genetics and Crop Plant Research, D-06466 Gatersleben, Germany)
IN:
Proc Natl Acad Sci U S A
2003; 100:998-1003
Impact Factor(s) of Proc Natl Acad Sci U S A: 10.452 (2004), 10.272 (2003), 10.7 (2002), 10.896 (2001)
ABSTRACT: Mouse embryonic stem (ES) cells differentiate into cells of all three primary germ layers including endodermal cells that produce insulin in vitro. We show that constitutive expression of Pax4 (Pax4(+)), and to a lesser extent Pdx1 (Pdx1(+)), affects the differentiation of ES cells and significantly promote the development of insulin-producing cells. In Pax4 overexpressing R1 ES cells, isl-1, ngn3, insulin, islet amyloid polypeptide, and glucose transporter 2 (Glut-2) mRNA levels increase significantly. The number of nestin-expressing (nestin+) cells also increases. Constitutive Pax4 expression combined with selection of nestin+ cells and histotypic culture conditions give rise to spheroids containing insulin-positive granules typical of embryonal and adult beta cells. In response to glucose, Pax4(+) and wild-type ES-derived cells release insulin. Transplantation of these cells into streptozotocin-treated diabetic mice results in a normalization of blood glucose levels. We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin.
TYPE OF PUBLICATION: Original article
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(Journal Article): In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.
Ianus A, Holz GG, Theise ND, Hussain MA (Department of Pathology, New York University School of Medicine, New York, New York 10016, USA)
IN:
J Clin Invest
2003; 111(6):843-850
Impact Factor(s) of J Clin Invest: 14.204 (2004), 14.307 (2003), 14.118 (2001)
ABSTRACT: Bone marrow harbors cells that have the capacity to differentiate into cells of nonhematopoietic tissues of neuronal, endothelial, epithelial, and muscular phenotype. Here we demonstrate that bone marrow-derived cells populate pancreatic islets of Langerhans. Bone marrow cells from male mice that express, using a CRE-LoxP system, an enhanced green fluorescent protein (EGFP) if the insulin gene is actively transcribed were transplanted into lethally irradiated recipient female mice. Four to six weeks after transplantation, recipient mice revealed Y chromosome and EGFP double-positive cells in their pancreatic islets. Neither bone marrow cells nor circulating peripheral blood nucleated cells of donor or recipient mice had any detectable EGFP. EGFP-positive cells purified from islets express insulin, glucose transporter 2 (GLUT2), and transcription factors typically found in pancreatic beta cells. Furthermore, in vitro these bone marrow-derived cells exhibit - as do pancreatic beta cells - glucose-dependent and incretin-enhanced insulin secretion. These results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus. The results generated with the CRE-LoxP system also suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.
TYPE OF PUBLICATION: Original article
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(Journal Article): Bone marrow-derived stem cells initiate pancreatic regeneration.
Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B, Thyssen S, Gray DA, Bhatia M (Robarts Research Institute, Stem Cell Biology and Regenerative Medicine, 100 Perth Drive, London, Ontario N6A 5K8, Canada)
IN:
Nat Biotechnol
2003; 21(7):763-770
Impact Factor(s) of Nat Biotechnol: 22.738 (2005), 22.355 (2004), 17.721 (2003), 12.822 (2002), 11.31 (2001)
ABSTRACT: We show that transplantation of adult bone marrow-derived cells expressing c-kit reduces hyperglycemia in mice with streptozotocin-induced pancreatic damage. Although quantitative analysis of the pancreas revealed a low frequency of donor insulin-positive cells, these cells were not present at the onset of blood glucose reduction. Instead, the majority of transplanted cells were localized to ductal and islet structures, and their presence was accompanied by a proliferation of recipient pancreatic cells that resulted in insulin production. The capacity of transplanted bone marrow-derived stem cells to initiate endogenous pancreatic tissue regeneration represents a previously unrecognized means by which these cells can contribute to the restoration of organ function.
TYPE OF PUBLICATION: Original article
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(Journal Article): Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin.
Kojima H, Nakamura T, Fujita Y, Kishi A, Fujimiya M, Yamada S, Kudo M, Nishio Y, Maegawa H, Haneda M, et al (Third Department of Medicine, Shiga University of Medical Science, Shiga, Japan)
IN:
Diabetes
2002; 51:1398-1408
Impact Factor(s) of Diabetes: 8.848 (2004), 8.298 (2003), 8.256 (2002), 7.7 (2001)
ABSTRACT: Immature rat intestinal stem cells (IEC-6) given the ability to express the transcription factor, pancreatic duodenal homeobox 1 (Pdx-1), yielded YK cells. Although these cells produced multiple enteroendocrine hormones, they did not produce insulin. Exposure of YK cells to 2 nmol/l betacellulin yielded BYK cells that showed the presence of insulin expression in cytoplasm and that secreted insulin into culture media. By examining the mechanism of differentiation in BYK cells, we found that another transcription factor, islet factor 1 (Isl-1) was newly expressed with the disappearance of Pax-6 expression in those cells after exposure to betacellulin. These results indicated that combined expression of Pdx-1 and Isl-1 in IEC-6 cells was required for the production of insulin. In fact, overexpression of both Pdx-1 and Isl-1 in IEC-6 cells (Isl-YK-12, -14, and -15 cells) gave them the ability to express insulin without exposure to betacellulin. Furthermore, implantation of the Isl-YK-14 cells into diabetic rats reduced the animals' plasma glucose levels; glucose levels dropped from 19.4 to 16.9 mmol/l 1 day after the injection of cells. As expected, the plasma insulin concentrations were 2.7 times higher in the diabetic rats injected with Isl-YK-14 cells compared to in controls. In summary, our results indicated that immature intestinal stem cells can differentiate into insulin-producing cells given the ability to express the transcription factors Pdx-1 and Isl-1.
TYPE OF PUBLICATION: Original article
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(Journal Article): NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice.
Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L (Section of Diabetes, Endocrinology & Metabolism, Departments of Medicine and Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA,
lchan@bcm.tmc.edu
)
IN:
Nat Med
2003; 9(5):596-603
Impact Factor(s) of Nat Med: 28.878 (2005), 31.223 (2004), 30.55 (2003), 28.74 (2002), 27.906 (2001)
ABSTRACT: To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immuno-electron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes.
TYPE OF PUBLICATION: Original article
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(Journal Article): Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells.
Zalzman M, Gupta S, Giri R, Berkovich I, Sappal BS, Karnieli O, Zern MA, Fleischer N, Efrat S (Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel)
IN:
Proc Natl Acad Sci U S A
2003; 100(12):7253-7258
Impact Factor(s) of Proc Natl Acad Sci U S A: 10.452 (2004), 10.272 (2003), 10.7 (2002), 10.896 (2001)
ABSTRACT: Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.
TYPE OF PUBLICATION: Original article
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(Journal Article): Cell replacement therapy for type 1 diabetes.
Efrat S (Dept of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel,
sefrat(at)post.tau.ac.il
)
IN:
Trends Mol Med
2002; 8(7):334-339
Impact Factor(s) of Trends Mol Med: 7.497 (2004), 9.848 (2003), 7.162 (2002)
ABSTRACT: Replacement of the insulin-producing pancreatic islet beta cells represents the ultimate treatment for type 1 diabetes. Recent advances in islet transplantation underscore the urgent need for developing alternatives to human tissue donors, which are scarce. Two possible approaches are the expansion of differentiated beta cells by reversible immortalization and the generation of insulin-producing cells from embryonic or adult stem cells. It is possible that new insights into endocrine pancreas development will ultimately lead to manipulation of progenitor-cell fate towards the beta-cell phenotype of insulin production, storage and regulated secretion. Both allogeneic and autologous surrogate beta cells are likely to require protection from recurring autoimmunity. This protection might take the form of tolerization, cell encapsulation, or cell engineering with immunoprotective genes. If successful, these approaches could lead to widespread cell replacement therapy for type 1 diabetes.
TYPE OF PUBLICATION: Original article
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(Journal Article): Encapsulated, genetically modified cells producing in vivo therapeutics.
Hauser O, Prieschl-Grassauer E, Salmons B (Research Institute for Virology and Biomedicine, University of Veterinary Medicine, Veterinaerplatz 1, A-1210 Vienna, Austria)
IN:
Curr Opin Mol Ther
2004; 6:412-420
Impact Factor(s) of Curr Opin Mol Ther: 3.117 (2004), 3.049 (2003), 2.463 (2002), 1.148 (2001)
ABSTRACT: The ability to implant genetically modified cells in immuno-isolating materials has much potential for therapeutic use. This review presents the different types of polymer that can be used for encapsulation of cells and the recent use of genetically modified, encapsulated and thus immunoprotected cells for the treatment of diseases in animal models and clinical trials. Some of the challenges faced by these technologies and potential solutions are also discussed.
TYPE OF PUBLICATION: Original article
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(Journal Article): A second pathway for regeneration of adult exocrine and endocrine pancreas.
Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE (Joslin Diabetes Center, Boston, MA 02215.)
IN:
Diabetes
1993; 42(12):1715-1720
Impact Factor(s) of Diabetes: 8.848 (2004), 8.298 (2003), 8.256 (2002), 7.7 (2001)
ABSTRACT: Substantial regeneration of both the endocrine and exocrine pancreas occurs after a 90% partial pancreatectomy in the young adult rat. We have reported previously that replication of preexisting islet and exocrine cells is enhanced 3- to 4-fold. Here, we report a second pathway of regeneration, that of proliferation and differentiation of precursor cells in the ductal epithelium. As shown with in vivo pulse labeling using 5-bromo-2'-deoxyuridine, an expansion of the ductal epithelium occurs. Proliferation is seen first in the common pancreatic duct and sequentially in smaller ducts of the ductal tree as focal areas of proliferation small ductules form. By 60 h after pancreatectomy, only these focal areas show heavy 5-bromo-2'-deoxyuridine staining. These proliferating ductules comprise 12.8% of the pancreatic volume at 3 days after pancreatectomy but are uncommon at 7 days after pancreatectomy. Coincident with the appearance and disappearance of these regions was a 3.5-fold increased growth of the pancreatic remnant compared with its equivalent of sham animals. These small ductules differentiate into new pancreatic islets and exocrine tissue, forming new lobules of pancreas that are indistinguishable from the preexisting ones. This second pathway of rapid regeneration recapitulates embryonic development in its pattern of ductal proliferation and subsequent differentiation. Furthermore, these studies provide evidence of the presence of precursor/stem cells in the adult pancreas.
TYPE OF PUBLICATION: Original article
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