Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote beta cell regeneration

Endogenous beta cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that beta cell recovery following hypervascularization-induced beta cell loss involves interactions with endothelial cells (ECs) and macrophages. Here we show that proliferative ECs modulate macrophage infiltration and phenotype during beta cell loss, and recruited macrophages are essential for beta cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during beta cell recovery and leads to increased beta cell proliferation without changes in macrophage phenotype or number. Transcriptome analysis of beta cells, ECs, and macrophages reveals that beta cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in beta cells. Collectively, these findings suggest a new beta cell regeneration paradigm whereby coordinated interactions between intra-islet macrophages, ECs, and extracellular matrix mediate beta cell self-renewal.