Endothelial progenitor cell transplantation attenuates synaptic loss associated with enhancing complement receptor 3-dependent microglial/macrophage phagocytosis in ischemic mice

Abstract

Endothelial progenitor cell (EPC) transplantation has therapeutic effects in cerebral ischemia. However, how EPCs modulate microglial activity remains unclear. In the study, we explored whether EPCs modulated microglial/macrophage activity and facilitated injured brain repair. Adult male mice (n = 184) underwent transient middle cerebral artery occlusion, and EPCs were transplanted into the brain immediately after ischemia. Microglial/macrophage activity and complement receptor 3 (CR3) expression were evaluated in ischemic brains and cultured microglia. CR3 agonist leukadherin-1 was administrated into mice immediately after ischemia to imitate the effects of EPCs. Synaptophysin and postsynaptic density protein 95 (PSD-95) expressions were detected in EPC- and leukadherin-1 treated mice. We found that EPC transplantation increased the number of M2 microglia/macrophage-phagocytizing apoptotic cells and CR3 expression in ischemic brains at 3 days after ischemia ( p < 0.05). EPC-conditional medium or cultured EPCs increased microglial migration and phagocytosis and upregulated CR3 expression in cultured microglia under oxygen-glucose deprivation condition ( p < 0.05). Leukadherin-1 reduced brain atrophy volume and neurological deficits at 14 days after ischemia ( p < 0.05). Both EPC transplantation and leukadherin-1 increased synaptophysin and PSD-95 expression at 14 days after ischemia ( p < 0.05). EPC transplantation promoted CR3-mediated microglial/macrophage phagocytosis and subsequently attenuated synaptic loss. Our study provided a novel therapeutic mechanism for EPCs.