Effects of the Insulted Neuronal Cells-Derived Extracellular Vesicles on the Survival of Umbilical Cord-Derived Mesenchymal Stem Cells following Cerebral Ischemia/Reperfusion Injury

Abstract

Umbilical cord-derived mesenchymal stem cells (UC-MSCs) engraftment is a potential therapy for cerebral ischemic stroke. However, the harsh microenvironment induced by cerebral ischemia/reperfusion restricts the survival rate and therapeutic efficiency of the engrafted UC-MSCs. In this study, we explored whether small extracellular vesicles (EVs) derived from injured neuronal cells following exposure to cerebral ischemia/reperfusion insult affect the survival of transplanted UC-MSCs. To establish a simulation of cerebral ischemia/reperfusion microenvironment comprising engrafted UC-MSCs and neuronal cells, we cocultured EVs derived from injured N2A cells, caused by exposure to oxygen-glucose deprivation and reperfusion (OGD/R) insult, with UC-MSCs in a conditioned medium. Coculture of UC-MSCs with EVs exacerbated the OGD/R-induced apoptosis and oxidative stress. Suppression of EVs-release via knock-down of Rab27a effectively protected the UC-MSCs from OGD/R-induced insult. Moreover, hypoxia preconditioning not only elevated the survival of UC-MSCs but also improved the paracrine mechanism of injured N2A cells. Altogether, these results show that EVs from injured N2A cells exacerbates OGD/R-induced injury on transplanted UC-MSCs in vitro. Hypoxia preconditioning enhances the survival of the engrafted-UC-MSCs; hence, thus could be an effective approach for improving UC-MSCs therapy in ischemic stroke.