Analysis of the plasticity of HNF1b-expressing cells in the embryonic and adult pancreas

Understanding how insulin-producing beta-cells are generated may help in the design of regenerative and cellular therapies for Type 1 and Type 2 diabetes, both characterized by loss, misfunction or insufficient number of beta-cells. Although endocrine progenitors expressing neurogenin3 (Ngn3) have been described to emerge from the vicinity of ductal structures during both pancreatic embryonic development and adult regeneration, there is currently no direct evidence that it is the cells of the pancreatic ductal epithelium that are truly direct precursors of such endocrine progenitors. Previous work in our laboratory identified the MODY5 gene product (HNF1b (Tcf2/vHNF1) as a specific ductal marker in the developing and adult pancreas. The study of expression of cell-specific molecular markers suggested a direct transition from Hnf1b+ to Ngn3-expressing cells. However ad genetic lineage tracing is needed to unequivocally clarify this relationship between the two cell types. Hence, a transgenic mouse was generated through BAC recombineering, where a tamoxifen responsive Cre recombinase was expressed under the control of the Hnf1b regulatory elements. Crossing this mouse line with a Rosa26R reporter line has provided us with a suitable model to label ductal cells at different developmental stages and chase them during embryonic or adult life. Our results reveal a selective expression of the transgene in virtually all epithelial expressing cells of the developing and adult pancreatic ductal tree. I will present lineage tracing studies aimed determining the fate of such ductal epithelial cells during different stages of the embryonic development of the pancreas, during the physiological aging process, and in models of pancreas regeneration. These results should shed light on the plasticity of pancreatic duct cells in the developing and adult pancreas.