Cell autonomous and non-cell autonomous regulation of beta cell mass expansion

Abstract

Diabetes mellitus affects approximately 150 million people worldwide. This disease is characterized by hyperglycemia resulting from dysfunctional pancreatic beta cells. Current treatments for diabetics are inadequate because they often do not prevent complications associated with the disease; therefore, considerable efforts are focused on derivation of beta cells from embryonic stem cells. Accomplishing this requires a precise understanding of beta cell development and the molecular control of beta cell expansion in vivo. We addressed these approaches in two ways: first, we analyzed the requirement for neural crest (NC) derivatives in regulating beta cell maturation and second, we determined that the transcription factor Foxd3 is required for beta cell mass expansion during pregnancy. The pancreas develops through a coordinated system of signals from both the endoderm and surrounding mesoderm. Little effort has been devoted to analyzing the role of ectodermally-derived NC that innervates the pancreas during embryogenesis. Our work illustrated that NC enters the pancreatic primordium around 10.25 dpc, shortly after pancreatic evagination from the foregut epithelium. Using a genetic ablation of NC derivatives in the pancreas, we showed, in agreement with published data, increased beta cell proliferation and insulin-positive area. Additionally, our work illustrated a novel requirement for this lineage; NC derivatives are required for beta cell maturation. Beta cell proliferation in adult mice is rare unless the mice are metabolically challenged, such as during pregnancy. Therefore, I chose to analyze the requirement for Foxd3 during pregnancy. Foxd3 is expressed in the pancreatic primordium beginning at 10.5 dpc and is localized predominantly to beta cells after birth. Virgin mice carrying a pancreas-specific deletion of Foxd3 are euglycemic; however, during pregnancy these mice become glucose intolerant. Several genes required for cell proliferation are misregulated in the absence of Foxd3 resulting in decreased beta cell proliferation and beta cell mass during pregnancy. Together, my thesis research illustrated the requirement for NC derivatives in controlling beta cell maturation and demonstrated a novel role for Foxd3 in beta cell mass expansion during pregnancy. The findings from both studies can be applied to cell-based therapies to treat diabetics.