Endothelial Cells Promote Pancreatic Stem Cell Activation During Islet Regeneration in Mice

Abstract

Objectives Diabetes is the clinical consequence of the loss of the majority of the β-cell population and failure to regenerate new pancreatic β cells. The current therapies based on β-cell replacement have failed to achieve β-cell renewal and thus, long-term insulin freedom. We have hypothesized that early rejection of endothelial elements within the islet grafts may seriously hamper islet regeneration in both native and islet grafts. Methods In the present study, we analyzed the role of endothelial cells to activate pancreatic stem cells during islet regeneration. Mice were pretreated with or without endothelial pharmacological ablation of endothelial cells, followed by an acute β-cell injury using a single intraperitoneal injection of streptozotocin. We performed comparative morphometric analyses of recovered pancreata on days 3, 7, 10, and 30 after streptozotocin injury, staining with bromodeoxyuridine (BrdU) for representative cell types, β cells, endothelial elements, and stem cells. Blood glucose levels were measured continuously after the injury to monitor the capacity for metabolic control. Results Morphometric analyses revealed an increasing number of cells over time to be stained with a stem cell and BrdU markers among animals only injured with streptozotocin but not with endothelial ablation. Notably, on day 10, stem cell markers were dramatically decrease nearly to basal levels, with appearance of numerous insulin-positive cells. Intact vessels with cobblestone-shaped endothelial elements were observed in direct proportion to the better outcomes, both by morphometric and by metabolic parameters. In contrast, fewer insulin-positive cells were observed in pancreata that had been ablated of endothelial cells showing extensive collapse of endocrine functions. Conclusions We observed that endothelial elements promoted stem cell proliferation and islet regeneration after a β-cell insult. We believe that preservation of endothelial cells positively affects the process of pancreatic regeneration.