The receptor tyrosine kinase c-Kit plays an integral role in maintaining b-cell mass and function. Although c-Kit receptor signaling promotes angiogenesis in multiple cell types, its role in islet vasculature is unknown. This study examines the effects of c-Kit-mediated vascular endothelial growth factor isoform A (VEGF-A) and islet vascularization on b-cell function and survival using in vitro cell culture and in vivo mouse models. In Increasing evidence suggests that c-Kit and its ligand, stem cell factor (SCF), are implicated in the regulation of angiogenesis.

Progenitor expansion during development is a highly regulated process dictating the final organ size, while expansion of specific progenitor populators can adjust the final cellular composition of the organ. Understanding factors involved in these pathways is required to develop cell-based therapies such as β-cell transplantation for conditions such as diabetes mellitus. One versatile factor controlling both processes as well as a network of other proteins involved in pancreatic and duodenal development is the transcription factor SOX9. This review will focus on a comparison of SOX9 function during progenitor expansion and differentiation in the developing pancreas and duodenum with specific focus on endocrine development. During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. SOX9 expression is eventually limited to a subset of ductal and centroacinar cells, hypothesized to be the pancreatic stem cell compartment. Similarly, during duodenal development, SOX9 is expressed in most early epithelial progenitors and becomes gradually restricted to proliferative progenitors in the lower crypts, as well as mature Paneth and enteroendocrine cells indicating some differences in functional roles. However, in both developmental contexts, SOX9 is involved in pathways responsible for cellular proliferation and differentiation, such as Notch and Wnt. With its adaptable and central function in progenitor control, SOX9 represents an attractive target for manipulation for in vitro progenitor expansion and differentiation meriting further investigation.

Our findings indicate that ALDH1(+) cells represent a pool of endocrine precursors in the developing human pancreas and that ALDH1 activity is required during endocrine cell differentiation. Inhibition of ALDH1-mediated retinoid signalling impairs human fetal islet cell differentiation and survival.