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Expression of Progenitor Cell Markers During Expansion of Sorted Human Pancreatic Beta Cells

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Functional pancreatic beta cell mass is dynamic and although fully differentiated, beta cells are capable of reentering the cell cycle upon appropriate stimuli. Stimulating regeneration-competent cells in situ is clearly the most desirable way to restore damaged tissue. Regeneration by dedifferentiation and transdifferentiation is a potential source of cells exhibiting a more developmentally immature phenotype and a wide differentiation potential. In this context and to gain a better understanding of the transformation induced in human beta cells during forced in vitro expansion, we focused on identifying differences in gene expression along with phenotypical transformation between proliferating and quiescent human beta cells. FACS-purified beta cells from three different human pancreata were cultured during 3–4 months (8–10 subcultures) on HTB-9 cell matrix with hepatocyte growth factor. Gene expression profiling was performed on cells from each subculture on “in-house” pancreas-specific microarrays consisting of 218 genes and concomitant morphological transformations were studied by immunocytochemistry. Immunocytochemical studies indicated a shift from epithelial to neuroepithelial cell phenotype, including progenitor cell features such as protein gene product 9.5 (PGP 9.5), Reg, vimentin, and neurogenin 3 protein expression. The expression of 49 genes was downregulated, including several markers of endocrine differentiation while 76 were induced by cell expansion including several markers of progenitor cells. Their pattern also argues for the transdifferentiation of beta cells into progenitor cells, demonstrating neuroepithelial features and overexpressing both PBX1, a homeodomain protein that can bind as a heterodimer with PDX1 and could switch the nature of its transcriptional activity, and neurogenin 3, a key factor for the generation of endocrine islet cells. Our study of the machinery that regulates human beta cell expansion and dedifferentiation may help elucidate some of the critical genes that control the formation of adult pancreatic progenitor cells and hence design targets to modify their expression in view of the production of insulin-secreting cells.
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Keywords: Beta cell expansion; DNA microarray; Gene expression; Human purified beta cell

Document Type: Review Article

Affiliations: 1: INSERM ERIT-M 0106 2: INSERM U459, Faculty of Medicine, Place de Verdun 59045 Lille, France

Publication date: February 1, 2005

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  • Gene Expression, The Journal of Liver Research will publish articles in all aspects of hepatology. Hepatology, as a research discipline, has seen unprecedented growth especially in the cellular and molecular mechanisms of hepatic health and disease, which continues to have a major impact on understanding liver development, stem cells, carcinogenesis, tissue engineering, injury, repair, regeneration, immunology, metabolism, fibrosis, and transplantation. Continued research and improved understanding in these areas will have a meaningful impact on liver disease prevention, diagnosis, and treatment. The existing journal Gene Expression has expanded its focus to become Gene Expression, The Journal of Liver Research to meet this growing demand. In its revised and expanded scope, the journal will publish high-impact original articles, reviews, short but complete articles, and special articles (editorials, commentaries, opinions) on all aspects of hepatology, making it a unique and invaluable resource for readers interested in this field. The expanded team, led by an Editor-in-Chief who is uniquely qualified and a renowned expert, along with a dynamic and functional editorial board, is determined to make this a premier journal in the field of hepatology.
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