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Promotion of β-Cell Differentiation in Pancreatic Precursor Cells by Adult Islet Cells

Department of Immunobiology and Internal Medicine (W.C., L.O.-A., J.G., T.F.G., A.L.M.B., K.C.H.), Yale University School of Medicine, New Haven, Connecticut 06520; and Department of Genetics and Development (S.B., V.E.P.), College of Physicians and Surgeons, Columbia University, New York, New York 10032

Address all correspondence and requests for reprints to: Kevan C. Herold, M.D., Department of Immunobiology, Yale University School of Medicine, 10 Amistad Street, 131D, New Haven, Connecticut 06520. E-mail: kevan.herold{at}yale.edu.

It is thought that differentiation of β-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify β-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed β-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or βTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into β-cells was induced by mature islet cells. It was specific for β-cells and not a general feature of endodermal derived cells. β-Cell differentiation required cell-cell contact. The induced cells acquired features of mature β-cells including increased expression of β-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature β-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of β-cells can be affected by other β-cells.

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