Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Neurology, Ruijin Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
J Cereb Blood Flow Metab. 2023 Mar;43(3):379-392. doi: 10.1177/0271678X221135841. Epub 2022 Dec 1.
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 ( < 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 (0.05). Leukadherin-1 reduced brain atrophy volume and neurological deficits at 14 days after ischemia (0.05). Both EPC transplantation and leukadherin-1 increased synaptophysin and PSD-95 expression at 14 days after ischemia (0.05). EPC transplantation promoted CR3-mediated microglial/macrophage phagocytosis and subsequently attenuated synaptic loss. Our study provided a novel therapeutic mechanism for EPCs.
内皮祖细胞（EPC）移植对脑缺血具有治疗作用。然而，EPC 如何调节小胶质细胞活性尚不清楚。在这项研究中，我们探讨了 EPC 是否调节小胶质细胞/巨噬细胞活性并促进受损大脑修复。成年雄性小鼠（n=184）接受短暂性大脑中动脉闭塞，缺血后立即将 EPC 移植到大脑中。评估缺血大脑和培养的小胶质细胞中的小胶质细胞/巨噬细胞活性和补体受体 3（CR3）表达。缺血后立即给予 CR3 激动剂白细胞粘附素-1 以模拟 EPC 的作用。在 EPC 和白细胞粘附素-1 处理的小鼠中检测突触小体蛋白和突触后密度蛋白 95（PSD-95）的表达。我们发现，EPC 移植可增加缺血后 3 天缺血大脑中 M2 小胶质细胞/巨噬细胞吞噬凋亡细胞的数量和 CR3 表达（<0.05）。EPC 条件培养基或培养的 EPC 在氧葡萄糖剥夺条件下增加小胶质细胞迁移和吞噬作用，并上调培养的小胶质细胞中 CR3 的表达（0.05）。白细胞粘附素-1 可减少缺血后 14 天的脑萎缩体积和神经功能缺损（0.05）。EPC 移植和白细胞粘附素-1 均可增加缺血后 14 天的突触小体蛋白和 PSD-95 表达（0.05）。EPC 移植促进了 CR3 介导的小胶质细胞/巨噬细胞吞噬作用，从而减轻了突触丢失。我们的研究为 EPC 提供了一种新的治疗机制。
