Abstract
Background: Evidences indicate that exosomes-mediated delivery of microRNAs (miRNAs or miRs) is involved in the neurogenesis of stroke. This study was to investigate the role of exosomal miRNAs in non-drug therapy of electro-acupuncture (EA) regulating endogenous neural stem cells for stroke recovery.Methods: The model of focal cerebral ischemia and reperfusion in rats were established by middle cerebral artery occlusion (MCAO) and treated by EA. The exosomes were extracted from peri-ischemic striatum and identified by exosomal biomarkers, and detected differentially expressed miRNAs with microarray chip. Primary stem cells were cultured, and oxygen–glucose deprivation and reperfusion (OGD/R) was used to mimic vitro ischemic injury.Results: The levels of exosomal biomarkers TSG101 and CD81 were increased in peri-ischemic striatum after EA treatment, and we revealed 25 differentially expressed miRNAs in isolated exosomes, of which miR-146b was selected for further analysis, and demonstrated that EA increased miR-146b expression and its inhibitors could block the effects. Subsequently, we confirmed that EA upregulated miR-146b expression to promote neural stem cells differentiation into neurons in peri-ischemic striatum. In vitro, it was verified that OGD/R hindered neural stem cells differentiation, and miR-146b inhibitors furtherly suppressed its differentiation, simultaneously NeuroD1 was involved in neural stem cells differentiation into neurons. Moreover, in vivo we found EA promoted NeuroD1-mediated neural stem cells differentiation via miR-146b. In addition, EA also could improve neurological deficits through miR-146b after ischemic stroke.Conclusion: EA promotes the differentiation of endogenous neural stem cells via exosomal miR-146b to improve neurological injury after ischemic stroke.
Highlights
Stroke remains the second-leading cause of death in the world, with ischemic stroke accounting for70% of all strokes, and approximately half of patients died or became disabled within 1–3 months (Wang et al, 2017; Wu et al, 2019)
The levels of exosomal biomarkers TSG101 and CD81 were increased in peri-ischemic striatum after EA treatment, and we revealed 25 differentially expressed miRNAs in isolated exosomes, of which miR-146b was selected for further analysis, and demonstrated that EA increased miR-146b expression and its inhibitors could block the effects
The results showed that the expression of miR-146b was decreased in the middle cerebral artery occlusion (MCAO)+miR-146b inhibitors group, while higher expression in the MCAO+EA group, which compared with the MCAO group (P < 0.01, Figure 1E)
Summary
Stroke remains the second-leading cause of death in the world, with ischemic stroke accounting for70% of all strokes, and approximately half of patients died or became disabled within 1–3 months (Wang et al, 2017; Wu et al, 2019). The endogenous neural stem cells of the adult brain are mainly present in the subventricular zone (SVZ) region of the lateral ventricle and the subgranular zone (SGZ) region of the hippocampus (Péron and Berninger, 2015; Boldrini et al, 2018). These neural stem cells could be activated and proliferated after stroke migrated into the lesion and differentiated into functional neural cells (Yamashita et al, 2006; Ngalula et al, 2015). This study was to investigate the role of exosomal miRNAs in non-drug therapy of electro-acupuncture (EA) regulating endogenous neural stem cells for stroke recovery
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