The pancreatic ?-cells are responsible for producing insulin and maintaining glucose homeostasis. A loss of ?-cells or their inability to compensate for insulin resistance is the major cause for type I and type 2 diabetes, respectively. Increasing ?-cell mass or generating optimally functional islets in vitro for transplantation could potentially improve or cure diabetic conditions. Thus, efforts have been focused on improving ?-cell mass by understanding and manipulating the mechanisms involved in their differentiation, proliferation and regeneration. PTEN is a lipid phosphatase that antagonizes the function of the PI3K signaling pathway. Targeted deletion of Pten in insulin producing cells led to a significant increase in total islet mass. This study suggests that ?-cell regeneration may be under mitogenic regulation and that PTEN may be regulating ?-cell regeneration in a paracrine fashion. To understand the biology underlying ?-cell regeneration, we performed immunohistological (IHC) analysis in a ?-cell injury and non-injury model. We demonstrated that the proliferating cells are most likely originating from previous-existing ?-cells under normal physiological conditions, but seem to induce proliferation of surrounding non-?-cells in the streptozotocin (STZ)-treated mice. To further confirm this observation, we used a reporter mouse model, Ptenlox/lox;Rosa26lacZ;Rip-Cre+, to determine the origin of the proliferating cells. Our preliminary analysis showed that the effect of PTEN on ?-cellproliferation may be intrinsic and that ?-cells themselves are contributing to ?-cell regeneration. However, when STZ was administered to these mice, the loss of PTEN in ?-cell produced a paracrine effect to induce a proliferation of surrounding non-beta-cells and non-islet cells. Further IHC analysis suggests that this loss of PTEN in ?-cells lead to the expansion of surrounding mesenchyme in these STZ-treated mice. Together, our present studies suggest that mitogenic signaling, such as those regulated by PTEN, may regulate ?-cell proliferation and regeneration under physiological conditions in a cell intrinsic manner, but may induce a paracrine effect during ?-cell injury.
Bayan, Jennifer-Ann Project Narrative This proposal aims at elucidating the mechanisms involved in the physiological regeneration of ?-cells. Loss of PTEN in the ?-cells resulted in a paracrine effect to induce the proliferative activity in the surrounding mesenchymes and these mesenchymal cells may support the regeneration of the islets. Identifying how the communication occurs may provide clinically relevant mechanism for inducing ?-cell regeneration and represents a great leap in regenerative medicine for the treatment of diabetes
|Bayan, Jennifer-Ann; Peng, Zhechu; Zeng, Ni et al. (2015) Crosstalk Between Activated Myofibroblasts and ? Cells in Injured Mouse Pancreas. Pancreas 44:1111-20|