Effects of extracellular vesicles from mesenchymal stem cells on oxygen-glucose deprivation/reperfusioninduced neuronal injury

BACKGROUND: Small extracellular vesicles (sEVs) from bone marrow mesenchymal stemcells (BMSCs) have shown therapeutic potential for cerebral ischemic diseases. However, themechanisms by which BMSC-derived sEVs (BMSC-sEVs) protect neurons against cerebral ischemia/reperfusion (I/R) injury remain unclear. In this study, we explored the neuroprotective effects ofBMSC-sEVs in the primary culture of rat cortical neurons exposed to oxygen-glucose deprivation andreperfusion (OGD/R) injury.METHODS: The primary cortical neuron OGD/R model was established to simulate the processof cerebral I/R in vitro. Based on this model, we examined whether the mechanism through whichBMSC-sEVs could rescue OGD/R-induced neuronal injury.RESULTS: BMSC-sEVs (20 μg/mL, 40 μg/mL) significantly decreased the reactive oxygenspecies (ROS) productions, and increased the activities of superoxide dismutase (SOD) and glutathioneperoxidase (GPx). Additionally, BMSC-sEVs prevented OGD/R-induced neuronal apoptosis in vivo, asindicated by increased cell viability, reduced lactate dehydrogenase (LDH) leakage, decreased terminaldeoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining-positivecells, down-regulated cleaved caspase-3, and up-regulated Bcl-2/Bax ratio. Furthermore, Westernblot and flow cytometry analysis indicated that BMSC-sEV treatment decreased the expression ofphosphorylated calcium/calmodulin-dependent kinase II (p-CaMK II)/CaMK II, suppressed the increaseof intracellular calcium concentration ([Ca2+]i) caused by OGD/R in neurons.CONCLUSIONS: These results demonstrate that BMSC-sEVs have signifi cant neuroprotectiveeff ects against OGD/R-induced cell injury by suppressing oxidative stress and apoptosis, and Ca2+/CaMK II signaling pathways may be involved in this process.