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Cell Journal، جلد ۱۷، شماره Suppl ۱، صفحات ۱۱-۱۲
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عنوان انگلیسی Is-6: Progress towards An Allogeneic Bank of Stem Cell Derived Islets for Transplantation in The Treatment of Diabetes
چکیده انگلیسی مقاله Objective: The overarching aim of the study was to generate a replenishable supply of islets of Langerhans that would meet the ever-increasing demand for transplantation in the treatment of type 1 diabetes. There are two main alternative sources of islets for transplantation: ES/iPSC-derived progenitors, and fully transdifferentiated Beta cells derived from adult tissue. In the case of the latter the adult tissue could be expanded as a mesenchymal cell population (MSC), and then induced to undergo a reversal of the epithelial to mesenchymal transition (EMT) to provide a source of tissue that could be reprogrammed or transdifferentiated. Materials and Methods: ES/iPS cells were differentiated into Beta-like cells following a protocol that recapitulates the pathway of development in the mouse, i.e. formation of definitive endoderm (DE), pancreatic progenitors, islet progenitors, and from there towards fully functional Beta cells. The protocol involves the sequential addition of the following factors: activin A to induce formation of DE, cyclopamine to induce foregut endoderm and mimic formation of the pancreatic anlage, retinoic acid and FGF to promote pancreatic morphogenesis, inhibition of activin signalling with SB431542 to block formation of liver lineages, Noggin to inhibit BMP signalling, and a gamma secretase inhibitor to inhibit exocrine and promote endocrine lineages. In the case of expanded adult tissue we have discovered that the EMT can be reversed by overexpressing KLF4. Results: ES/iPS can be induced to differentiate towards Beta cell progenitors and functional Beta cells. The cells exhibit many of the properties of human adult Beta cells, including the ability to rescue diabetes in diabetic mouse models. Reversing the EMT that adult pancreatic tissue undergoes when placed in culture has proved more challenging. The amylase expressing acinar cells and residuals insulin expressing Beta cells can be genetically tagged with dsRED. The resulted AMY-Red and INS-Red MSCs were then expanded and FACs purified. Both populations could be differentiated into dsREDlabelled chondrocytes, osteocytes and adipocytes. We have further shown that KLF4 can induce a transient reversal of the EMT process, showing that both AMYRed and INS-Red MSCs can be induced to express insulin, although at very low levels.Conclusion: These results suggest that the goal of creating allogeneic banks of tissue typed Beta cells may be in sight. Avoiding the use of pluripotent cells, may have many translational advantages in terms of safety and complexity (cost/reproducibility) of the differentiation protocol.
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نویسندگان مقاله k docherty | k docherty


نشانی اینترنتی http://celljournal.org/journal/article/abstract/30
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