Abstract
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.
Highlights
Stroke is one of the major health threats worldwide with high mortality and morbidity, leading to ~5 million deaths per year[1]
To test the role of Extracellular vesicles (EVs) in Endothelial cells (ECs)-mediated neuronal protection, we set up a coculture system of human umbilical vein endothelial cells (HUVECs) and primary hippocampal neurons treated by oxygen-glucose deprivation (OGD) in the absence or presence of GW4869, a neutral sphingomyelinase inhibitor that blocks the secretion of exosomes[35] (Fig. 1a)
The result showed that OGD led to an increase of neuronal apoptosis, which was ameliorated by coculture with HUVECs
Summary
Stroke is one of the major health threats worldwide with high mortality and morbidity, leading to ~5 million deaths per year[1]. Rapid deprivation of oxygen and nutrients immediately after ischemia, as well as the following reperfusion damage in many cases, lead to massive necrotic and apoptotic neuronal death attributed to Extracellular vesicles (EVs), including microvesicles, ectosomes, exosomes, apoptotic bodies, and so on, are highly heterogeneous membranous vesicles with lipid bilayer and various cargos, and are suggested as novel mediators of intercellular communication[7]. EVs exert their functions by transmitting their cargos including proteins, nucleic acids, and lipid molecules, into recipient cells[10,11,12]. After secretion into various body fluids including blood, cerebrospinal fluid, urine, saliva, and breast milk, EVs are internalized by recipient cells by mechanisms similar to receptor–ligand interaction[13]. Phagocytosis, and/or direct fusion, EVs/exosomes are able to deliver their cargos into cytosol, and thereby modify the physiological states of recipient cells[8]
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