|Budget Amount *help
¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000)
Fiscal Year 2004: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
Fiscal Year 2003: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
Fiscal Year 2002: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
By combining flow cytometry and clonal analysis, we show that a candidate pancreatic stem cell and progenitor population that reside in the developing mouse pancreas expresses the receptor for the hepatocyte growth factor c-Met, but do not express hematopoietic and vascular endothelial antigens such as CD45, TER119, c-Kit, and Flk-1, which formed clonal colonies in vitroand differentiated into multiple pancreatic lineage cells. Some of them could expand with self-renewal cell divisions in culture, and following cell transplantation, they differentiated into pancreatic islet and acinar cells in vivo. By using this antigen, pancreatic stem cells can be isolated prospectively, enabling a detailed investigation of stem cell markers, and application towards regenerative therapies for diabetes mellitus.
Glucagon-like peptide (GLP)-1 is produced through posttranslational processing of proglucagon and acts as a regulator of various homeostatic events. Among its analogs, however, the function of GLP-1-(1-37), synthesized in small amounts in the pancreas, has been unclear. We find that GLP-1-(1-37) induces insulin production in developing and, to a lesser extent, adult intestinal epithelial cells in vitro and in vivo, a process mediated by upregulation of the Notch-related gene ngn3 and its downstream targets, which are involved in pancreatic endocrine differentiation. These cells became responsive to glucose challenge in vitro and reverse insulin-dependent diabetes after implantation into diabetic mice. Our findings suggest that efficient induction of insulin production in intestinal epithelial cells by GLP-1-(1-37) could represent a new therapeutic approach to diabetes mellitus.