Interplay between FGF10 and Notch signalling is required for the self-renewal of pancreatic progenitors

Abstract

Recent studies have shown that persistent expression of FGF10 in the developing pancreas of transgenic mice results in enhanced and prolonged proliferation of pancreatic progenitors, pancreatic hyperplasia and impaired pancreatic differentiation. These studies have also suggested that FGF10 prevents the differentiation of pancreatic progenitors by maintaining persistent Notch signalling. Here, we provide experimental evidence sustaining the capacity of FGF10 to induce the proliferation of pancreatic precursors, while preventing their differentiation. Using explant cultures of E10.5 isolated dorsal pancreatic epithelium, we found that FGF10 maintained Notch activation and induced the expansion of pancreatic precursors while blocking their differentiation. In addition, by using a γ-secretase inhibitor, we were able to down-regulate the expression of Hes1, a target gene of the Notch pathway in explant cultures of pancreatic epithelium treated with FGF10. In such explants, the effect of FGF10 on the proliferation and maintenance of pancreatic progenitors was suppressed. These results demonstrate that activation of the Notch pathway is required as a downstream mediator of FGF10 signalling in pancreatic precursor cells.

Control of β-Cell Differentiation by the Pancreatic Mesenchyme

“…Comparisons of their phenotype with that of mice deficient in ␤-catenin suggest that Wnt1 overexpression at early development stages may reflect alternative roles for Wnt signaling, such as specifying the fate of the intestine (39). Difference in the stage of development of the explants could also explain the differences between our study and the one by Miralles et al (35). We used E13.5 rat pancreas, whereas Miralles et al used E10 mouse pancreas.…”

“…However, in transgenic mice ectopically expressing FGF10 in the pancreatic epithelium, epithelial cell proliferation increased but pancreatic differentiation of all cell types was markedly decreased (18,19). Such a phenotype was also observed when E10 mouse pancreatic epithelium was cultured in matrigel in the presence of FGF10 (35). This inhibition of differentiation was unexpected, and the contradiction between the phenotype of FGF10-deficient mice and transgenic mice with ectopic FGF10 expression or E10 mouse pancreatic epithelium grown with FGF10 was unexplained.…”

“…Moreover, glucagon-expressing cells did not form prematurely or in excess (17). In contrast, endocrine cell differentiation was strongly inhibited in transgenic mice overexpressing FGF10 or in E10 mouse pancreatic epithelium grown with FGF10 (18,19,35). One hypothesis for explaining these apparent contradictions involves the timing of FGF10 expression in transgenic mice.…”

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

“…5-11.5 (56). In fact, inhibition of Notch cleavage by a g-secretase inhibitor renders cells nonresponsive to the proliferative effects of FGF10 (57)(58)(59).…”

Derivation of Insulin-Producing Beta-Cells from Human Pluripotent Stem Cells

“…In contrast, transgenic mice over-expressing FGF10 display pancreatic hyperplasia resulting from reduced differentiation and associated expansion of pancreatic progenitor cell numbers [60,61]. A similar proliferative effect of FGF10 on pancreatic progenitor cells has been also been demonstrated in vitro in both isolated rat [62] and mouse [63] pancreatic epithelia. The addition of FGF10 to E10.5 mouse pancreatic epithelium increased the proliferation of pancreatic progenitors.…”