222-LB: Canonical Wnt Signaling Regulates Beta-Cell Neogenesis from Pancreatic Duct Cells

Abstract

Diabetes results from loss or insufficient numbers of insulin producing beta cells. Thus, restoration of beta cell mass can offer a lasting cure for diabetes. Physiological conditions such as obesity and pregnancy are known to induce compensatory increase in beta cell mass; suggesting the presence of an endogenous mechanism for beta cell regeneration. Significant progress has been made in understanding the regeneration of beta-cells through proliferation of existing beta-cells. In addition to proliferation of existing beta-cells, there is mounting evidence, from both animal models and human tissue, indicating that adult pancreatic duct cells can regenerate endocrine cells, including insulin producing cells. However, the molecular mechanisms governing the regeneration of pancreatic endocrine cells, especially beta cell from pancreatic duct cells remain to be defined. We have found that adult pancreatic duct cells are active in both Notch and Wnt/beta-catenin signaling. Transcriptional profiling revealed Hes1 as the predominant Notch target gene in adult mouse pancreatic duct cells. Using lineage-tracing mouse models, we found that duct-specific deletion of Hes1 in vivo resulted in the conversion of pancreatic duct cells into predominantly somatostatin+ cells. Conversely, pancreatic duct-specific deletion of the canonical Wnt signaling effector, beta-catenin, in vivo resulted in downregulation of Hes1 expression, and the conversion of pancreatic duct cells into predominantly insulin producing cells. Taken together our results demonstrate that Notch and Wnt signaling maintain the adult pancreatic duct state, with duct-derived beta-cell neogenesis requiring the loss of Wnt/beta-catenin signaling. Disclosure S. Afelik: None. Z. Yu: None.