2. Pancreas development
In the embryo, the pancreas develops as an outgrowth of the endoderm which is the cell layer that delineates the primitive gut. 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 cells that produce insulin, glucagon, somatostatin, pancreatic polypeptide or ghrelin. The endocrine cells associate to form the islets of Langerhans. Our group investigates the transcriptional mechanisms and signal transduction pathways that control how endoderm cells become pancreatic precursors and how the latter develop into endocrine precursor cells.
We found that the Onecut transcription factors and FGF signaling control development of pancreatic progenitors from the endoderm, and the subsequent generation of endocrine precursor cells. This research is currently pursued using the mouse, including transgenic mice, as a model organism.
Embryos that are wild-type or knockout for HNF-6 and/or FGF-10 were immunostained for the pancreatic marker Pdx1 (brown staining). The embryos were analysed at the onset of pancreas development and a blow-up of the abdominal region is shown with arrows pointing to the pancreatic buds. The size of the pancreatic buds is reduced in hnf6-/- and fgf10-/- embryos; in double knockouts the pancreas does not develop.
The characterization of the cellular and molecular mechanisms that control the stepwise differentiation of endocrine cells from progenitor cells is essential for the development of cell therapy of diabetes. Therefore, our work is performed in collaboration with national and foreign research teams who attempt to transpose the knowledge gained from fundamental studies to programmed differentiation of stem cells to insulin-producing cells. These collaborations include our participation to the EU-sponsored network BetaCellTherapy.
Our work in pancreas development also addresses how pancreatic ducts are generated. These ducts drain the secretions from the pancreatic exocrine cells to the intestine and are delineated by ductal cells. Work by our and other teams has provided evidence that ductal cells can transdifferentiate to endocrine cells. Current work investigates the transcriptional mechanisms that govern this transdifferentiation process.
Moreover, our research on the role of the Onecut transcription factor OC-1/HNF-6 uncovered that this protein is essential to control the size of the pancreatic ducts. In the absence of HNF-6, ducts form pancreatic cysts devoid of cilia. This work parallels that of our group on bile duct development. The transcriptional and signaling networks that control pancreatic duct development are further being investigated. This work bears significance for the understanding of the pathophysiology of polycystic diseases.
HNF-6 (red staining) marks the nuclei of developing pancreatic ducts. Green : Mucin-1 (green staining) at apical pole of cells delineate the lumens.
To know more... (pdf chapter of the last de Duve Institute report)
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