Neural stem cell-derived exosomes improve neurite outgrowth and cognitive function through transferring miR-132-3p.

Objective: Vascular dementia (VD) is accompanied by severe neuronal damage. Exosomal microRNAs (miRs) have been implicated in the neuroprotective effect of neural stem cells (NSCs), and miR-132-3p is a proneurogenic miR. In this study, we aimed to explore the role and underlying mechanisms of miR-132-3p-enriched NSC-EXs in VD-induced neuronal damage and synaptic impairment.

Methods: NSC-EXs, NSC-EXs enriched with miR-132-3p (NSC-EXsmiR-132-3p), and NSC-EXs deficient in miR-132-3p (NSC-EXssimiR-132-3p) were cocultured with oxygen- and glucose-deprived (OGD)-injured neurons or administered to VD mice. Bioinformatic analyses and luciferase assays were used to determine the target genes of miR-132-3p.

Results: The levels of NSC-EXs and their associated miR-132-3p were markedly decreased in the hippocampi of VD mice. Compared with NSC-EXs, the infusion of NSC-EXsmiR-132-3p was more effective at increasing the miR-132-3p level, neuron number, dendritic spine density and cognitive function and decreasing neuronal ROS production and apoptosis, whereas NSC-EXssimiR-132-3p treatment resulted in attenuated effects in comparison with those of NSC-EXs. In OGD-treated neurons, incubation with NSC-EXsmiR-132-3p increased neurite outgrowth and decreased neuronal ROS production and apoptosis. Moreover, through bioinformatic analysis and cell transfection, we confirmed that NSC-EXsmiR-132-3p promoted neurite outgrowth by targeting RASA1 and increasing the expression of downstream Ras and the phosphorylation of ERK1/2.

Conclusions: Our findings indicate that miR-132-3p enrichment promotes the efficacy of NSC-EXs in treating VD-induced neuronal damage and synaptic impairment via the inhibition of RASA1 and the activation of the downstream Ras/ERK1/2 signaling pathway.