Endocrine Abstracts

A longstanding unsettled question is whether pancreatic β-cells originate from exocrine duct cells. We have now used a genetic labeling approach to fate map embryonic and adult pancreatic duct cells. We employed a BAC genomic clone containing the Hnf1b locus to generate a transgenic mouse line that expresses a hormone-inducible form of Cre in pancreatic ducts. We verified that in this model Cre is specifically expressed throughout the pancreatic duct epithelium, in virtually all cells expressing Hnf1β, and showed that Cre-induced recombination of a reporter locus is strictly hormone-dependent. We subsequently performed lineage tracing analysis of Hnf1β⁺ duct cells of the developing and adult pancreas. We show that Hnf1β⁺ cells of the early branching pancreas contribute to acinar, duct, and endocrine lineages. Hnf1β⁺ cells thereafter form the embryonic duct epithelium that gives rise to both ductal and endocrine lineages, but not to acinar cells. By the end of gestation, however, the fate of Hnf1β⁺ duct cells is restricted. We provide compelling evidence that the differentiated duct epithelium does not make a significant contribution to acinar or endocrine cells during neonatal growth, during a 6-month observation period, or during growth of β-cells that follows the ligation of the pancreatic duct or the ablation of β-cells followed by EGF and gastrin treatment. Thus, once the ductal epithelium differentiates it has a restricted plasticity, even under regenerative settings.