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Control of Beta-Cell Differentiation by the Pancreatic Mesenchyme

¹ University Paris-Descartes, Faculty of Medicine; INSERM, Necker Hospital, EMI 363, 75730 Paris cedex 15, France
² Genethon-CNRS UMR 8115, Evry, France

Correspondence: scharfmann{at}necker.fr

The importance of mesenchymal-epithelial interactions for normal development of the pancreas was recognized in the early 1960s, and mesenchymal signals have been shown to control the proliferation of early pancreatic progenitor cells. The mechanisms by which the mesenchyme coordinates cell proliferation and differentiation to produce the normal number of differentiated pancreatic cells are not fully understood. Here, we demonstrate that the mesenchyme positively controls the final number of beta cells that develop from early pancreatic progenitor cells. In vitro, the number of beta cells that developed from rat embryonic pancreatic epithelia was larger in cultures with mesenchyme than without mesenchyme. The effect of mesenchyme was due, not to an increase in beta cell proliferation, but to increased proliferation of early-PDX1-positive progenitor cells, as confirmed by BrdU incorporation. Consequently, the window during which early PDX1-positive pancreatic progenitor cells differentiated into endocrine progenitor cells expressing Ngn3 was extended. FGF10 mimicked mesenchyme effects on proliferation of early PDX1-positive progenitor cells and induction of Ngn3 expression. Taken together, our results indicate that expansion of early PDX1-positive pancreatic progenitor cells represents a way to increase the final number of beta cells developing from early embryonic pancreas.

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