Zhang Li, Li Chao, Huang Rui, Teng Hua, Zhang Yi, Zhou Min, Liu Xiangshuang, Fan Baoyan, Luo Hao, He Annie, Zhao Anna, Lu Mei, Chopp Michael, Zhang Zheng Gang
Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.
Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, United States.
Front Aging Neurosci. 2022 Jul 14;14:926485. doi: 10.3389/fnagi.2022.926485. eCollection 2022.
Small extracellular vesicles (sEVs) mediate cell-cell communication by transferring their cargo biological materials into recipient cells. Diabetes mellitus (DM) induces cerebral vascular dysfunction and neurogenesis impairment, which are associated with cognitive decline and an increased risk of developing dementia. Whether the sEVs are involved in DM-induced cerebral vascular disease, is unknown. Therefore, we studied sEVs derived from cerebral endothelial cells (CEC-sEVs) of aged DM rats (DM-CEC-sEVs) and found that DM-CEC-sEVs robustly inhibited neural stem cell (NSC) generation of new neuroblasts and damaged cerebral endothelial function. Treatment of aged DM-rats with CEC-sEVs derived from adult healthy normal rats (N-CEC-sEVs) ameliorated cognitive deficits and improved cerebral vascular function and enhanced neurogenesis. Intravenously administered N-CEC-sEVs crossed the blood brain barrier and were internalized by neural stem cells in the neurogenic region, which were associated with augmentation of miR-1 and -146a and reduction of myeloid differentiation primary response gene 88 and thrombospondin 1 proteins. In addition, uptake of N-CEC-sEVs by the recipient cells was mediated by clathrin and caveolin dependent endocytosis signaling pathways. The present study provides and evidence that DM-CEC-sEVs induce cerebral vascular dysfunction and neurogenesis impairment and that N-CEC-sEVs have a therapeutic effect on improvement of cognitive function by ameliorating dysfunction of cerebral vessels and increasing neurogenesis in aged DM rats, respectively.
小细胞外囊泡（sEVs）通过将其携带的生物物质转移到受体细胞中来介导细胞间通讯。糖尿病（DM）会导致脑血管功能障碍和神经发生受损，这与认知能力下降以及患痴呆症风险增加有关。sEVs是否参与糖尿病诱导的脑血管疾病尚不清楚。因此，我们研究了老年糖尿病大鼠脑内皮细胞来源的sEVs（DM-CEC-sEVs），发现DM-CEC-sEVs强烈抑制神经干细胞（NSC）生成新的神经母细胞，并损害脑内皮功能。用成年健康正常大鼠脑内皮细胞来源的sEVs（N-CEC-sEVs）治疗老年糖尿病大鼠可改善认知缺陷，改善脑血管功能并增强神经发生。静脉注射的N-CEC-sEVs穿过血脑屏障并被神经发生区域的神经干细胞内化，这与miR-1和-146a的增加以及髓样分化初级反应基因88和血小板反应蛋白1蛋白的减少有关。此外，受体细胞对N-CEC-sEVs的摄取是由网格蛋白和小窝蛋白依赖性内吞信号通路介导的。本研究提供了证据表明DM-CEC-sEVs诱导脑血管功能障碍和神经发生受损，而N-CEC-sEVs分别通过改善老年糖尿病大鼠脑血管功能障碍和增加神经发生对改善认知功能具有治疗作用。
