Neurons can upregulate Cav-1 to increase intake of endothelial cells-derived extracellular vesicles that attenuate apoptosis via miR-1290
Neurons can upregulate Cav-1 to increase intake of endothelial cells-derived extracellular vesicles that attenuate apoptosis via miR-1290
复制标题
神经元可以上调 Cav-1，以增加内皮细胞来源的细胞外囊泡的摄入量，从而通过 miR-1290 减弱细胞凋亡
DOI：
10.1038/s41419-019-2100-5
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发表时间：
2019-11-18
影响因子：
9
通讯作者：
Han, Hua
中科院分区：
文献类型：
--
作者：
Yue, Kang-Yi;Zhang, Pei-Ran;Han, Hua
细胞外小泡(包括外体)在生理和病理条件下都可以作为细胞间通讯的媒介。然而，电动汽车携带的货物分子发挥其功能，以及它们调节释放和摄取的机制一直知之甚少。在这项研究中，我们研究了内皮细胞来源的EVS对遭受缺氧-葡萄糖剥夺(OGD)的神经元的影响，OGD模拟人类疾病中的神经元缺血-再灌注损伤。在人脐静脉内皮细胞(HUVEC)-神经元共培养实验中，我们发现HUVEC减少了OGD条件下神经元的凋亡，这一作用可被外切体释放阻断剂GW4869所拮抗。纯化的EVS可被神经元内化，减轻OGD时神经元的凋亡。MiR-1290在HUVECs来源的EVS中高度富含，在OGD条件下负责EV介导的神经元保护作用。有趣的是，我们发现OGD增加了体外培养的神经元对EVS的摄取。我们检测了EV摄入的几种潜在受体的表达，发现在OGD处理的神经元和大脑中动脉阻塞(MCAO)的小鼠中，小窝蛋白-1(Cav-1)表达上调。在OGD条件下，下调神经元Cav-1的表达可减少EV摄取，并取消EV介导的神经元保护作用。HUVEC来源的EVS在体内减轻MCAO诱导的神经细胞凋亡。这些发现表明，缺血可能通过上调神经元Cav-1的表达来增加EV的摄取，从而通过miR-1290减少细胞凋亡来保护神经元。
Extracellular vesicles (EVs) including exosomes can serve as mediators of cell-cell communication under physiological and pathological conditions. However, cargo molecules carried by EVs to exert their functions, as well as mechanisms for their regulated release and intake, have been poorly understood. In this study, we examined the effects of endothelial cells-derived EVs on neurons suffering from oxygen-glucose deprivation (OGD), which mimics neuronal ischemia-reperfusion injury in human diseases. In a human umbilical endothelial cell (HUVEC)-neuron coculture assay, we found that HUVECs reduced apoptosis of neurons under OGD, and this effect was compromised by GW4869, a blocker of exosome release. Purified EVs could be internalized by neurons and alleviate neuronal apoptosis under OGD. A miRNA, miR-1290, was highly enriched in HUVECs-derived EVs and was responsible for EV-mediated neuronal protection under OGD. Interestingly, we found that OGD enhanced intake of EVs by neurons cultured in vitro. We examined the expression of several potential receptors for EV intake and found that caveolin-1 (Cav-1) was upregulated in OGD-treated neurons and mice suffering from middle cerebral artery occlusion (MCAO). Knock-down of Cav-1 in neurons reduced EV intake, and canceled EV-mediated neuronal protection under OGD. HUVEC-derived EVs alleviated MCAO-induced neuronal apoptosis in vivo. These findings suggested that ischemia likely upregulates Cav-1 expression in neurons to increase EV intake, which protects neurons by attenuating apoptosis via miR-1290.