Like the liver, the pancreas develops as an outgrowth of the endoderm. Pancreatic progenitors derived from the endoderm form two buds (dorsal and ventral) which later fuse to form a single organ. Within these buds the progenitor cells give rise, through a stepwise process, to endocrine, acinar and duct cells. Our group investigates the molecular mechanisms that control development of the various pancreatic cell types.
In collaboration with the CELL research group, we investigated the role of blood vessels in pancreas development, and uncovered the existence of a VEGF-dependent cross-talk between the blood vessels and the pancreatic epithelium which determines acinar differentiation of epithelial cells.
Development of blood vessels in normal mouse pancreas at embryonic day 15.5. The blood vessels (red) surround the basis of epithelial extrusions (green) which develop into acinar cells. The location of the vessels is determined by localized secretion of VEGF by the epithelial cells. Ectopic expression of VEGF at the tip of epithelial extrusions relocates the vessels around the tips and inhibits acinar differentiation (from Pierreux et al. Endothelial cross-talk regulates exocrine differentiation in developing pancreas Dev. Biol. 347, 216-227, 2010).
Moreover, our research on the role of the Onecut transcription factor
OC-1/HNF-6 uncovered that this protein is required for development of endocrine cells and pancreatic ducts. In the absence of HNF6, endocrine cells fail to develop in the embryo and ducts form cysts. Current work is focused on the potential role of OC-1/HNF-6 in acinar-to-ductal metaplasia , a lesion often preceding human pancreatic ductal adenocarcinoma and in which OC-1/HNF-6 is ectopically expressed in acinar cells. Finally, we also investigate the role of microRNAs that are linked with OC-1/HNF-6 in gene cascades that control pancreatic cell differentiation.
When the pancreatic duct is ligated in the pancreas, acinar-to-ductal plate metaplasia (ADM) is induced. Development of ADM is impaired in HNF6-knockout mice (from Prévot et al. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut, in press, 2012).