| dc.description.abstract | Reduced pancreatic β cell mass is a hallmark of diabetes, which makes the ability to increase or restore β cell mass a major therapeutic goal. While testing the hypothesis that increased endothelial cell signaling would increase β cell mass using a model of inducible vascular endothelial growth factor-A (VEGF-A) overexpression in β cells (βVEGF-A mouse), we found that increased VEGF-A leads to reduced, not increased, β cell mass. Surprisingly, withdrawal of the VEGF-A stimulus is followed by robust β cell proliferation, leading to islet regeneration, normalization of β cell mass, and reestablishment of the intra-islet capillary network. Using islet and bone marrow transplantation approaches we found that β cell proliferation is dependent on the local microenvironment of endothelial cells, β cells, and bone marrow-derived macrophages recruited to the islets upon VEGF-A induction. Depleting macrophages greatly reduced β cell proliferation, indicating that these macrophages are required for the β cell proliferative response in regenerating islets. Based on these data, in addition to transcriptome analysis of FACS-sorted islet β cell, and islet-derived endothelial cell and macrophage populations during VEGF-A induction and normalization, we propose a new paradigm for β cell regeneration where β cell self-renewal is mediated by coordinated interactions between macrophages recruited to the site of β cell injury, intra-islet endothelial cells, and β cells. In this model, (1) increased growth factors produced by β cells, endothelial cells, macrophages, (2) increased production of growth factor receptors and integrins on β cells, and (3) increased integrin activation by the extracellular matrix cause simultaneous, and potentially synergistic, activation of the PI3K/Akt and MAPK signaling pathways, leading to β cell proliferation. | |
