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The Mesenchyme Controls the Timing of Pancreatic ß-Cell Differentiation

¹ Université Paris-Descartes, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale, E363, Hôpital Necker, Paris, France
² Centre National de la Recherche Scientifique UMR7091, Hôpital Pitié Salpêtrière, Paris, France

Address correspondence and reprint requests to Bertrand Duvillié, Institut National de la Santé et de la Recherche Médicale, E363 Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France. E-mail: duvillie{at}necker.fr

Abbreviations: EGF, epidermal growth factor; FGF, fibroblast growth factor; Hes, Hairy and Enhancer-of-Split family; Ngn3, neurogenin3

The importance of mesenchymal-epithelial interactions in the proliferation of pancreatic progenitor cells is well established. Here, we provide evidence that the mesenchyme also controls the timing of ß-cell differentiation. When rat embryonic pancreatic epithelium was cultured without mesenchyme, we found first rapid induction in epithelial progenitor cells of the transcription factor neurogenin3 (Ngn3), a master gene controlling endocrine cell-fate decisions in progenitor cells; then ß-cell differentiation occurred. In the presence of mesenchyme, Ngn3 induction was delayed, and few ß-cells developed. This effect of the mesenchyme on Ngn3 induction was mediated by cell-cell contacts and required a functional Notch pathway. We then showed that associating Ngn3-expressing epithelial cells with mesenchyme resulted in poor ß-cell development via a mechanism mediated by soluble factors. Thus, in addition to its effect upstream of Ngn3, the mesenchyme regulated ß-cell differentiation downstream of Ngn3. In conclusion, these data indicate that the mesenchyme controls the timing of ß-cell differentiation both upstream and downstream of Ngn3.

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