The Role of Connective Tissue Growth Factor in Islet Morphogenesis and Beta Cell Proliferation

Abstract

Pancreatic beta cells are the only cell type in the body that can produce insulin, a hormone required for maintaining glucose homeostasis. Type 1 and type 2 diabetes result from an absolute or relative reduction in functional beta cell mass, respectively. One approach to replacing lost beta cell mass is transplantation of islets from cadaveric donors; however, this approach is limited by lack of adequate amounts of donor tissue. Therefore, there has been much interest in identifying factors that enhance beta cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in pancreatic endothelial cells, beta cells, and ducts during pancreas development. CTGF is required for proper lineage allocation and islet morphogenesis during development and for beta cell proliferation at late gestation. The current study investigated the tissue interactions by which CTGF promotes normal pancreatic islet development. These results show that CTGF produced by both endothelial cells and beta cells is required for embryonic beta cell proliferation, making CTGF the first identified secreted endothelial-derived or beta cell-derived factor which regulates embryonic beta cell proliferation. Removing CTGF from any one source in the pancreas impairs embryonic beta cell proliferation, indicating that beta cell proliferation is particularly sensitive to the level of CTGF. In contrast, inactivating CTGF from one source in the pancreas does not affect lineage allocation or islet morphogenesis, indicating that these sources of CTGF act redundantly to promote these processes. This dissertation also demonstrated that over-expression of CTGF in beta cells during embryogenesis using an inducible transgenic system increases islet mass by promoting endocrine cell proliferation. Together, these findings demonstrate that CTGF acts in both an autocrine and paracrine manner during pancreas development and suggest that CTGF has the potential to enhance beta cell proliferation or differentiation in diabetic models.