Mechanism of Neural Stem Cell-Derived Exosomal miR-9a-5p Overexpression Improving Survival and Neurogenesis in Ischemic Stroke Rats

Abstract

As a momentous condition disease, ischemic stroke could lead to physical disability and death. Here, the protective effect of miRNA up-regulated in neural stem cells (NSCs) derived exosomes on ischemic stroke in rats and their molecular mechanisms were investigated to reveal the therapeutic target of exosomes and suggests new approaches to treat ischemic stroke. miRNAs differentially expressed in exosomes derived from NSCs at various differentiation stages were detected by high-throughput sequencing for miRNAs. The impacts of miR-9a-5p upregulation were assessed on the differentiation of NSCs. The effects of exosomes derived from normal NSCs and NSCs with up-regulated miR-9a-5p on cell survival and differentiation and AMPK activation were investigated in vitro and in vivo. The high-throughput sequencing analysis revealed that miR-9a-5p was differentially expressed in NSC-derived exosomes at various stages of differentiation. MiR-9a-5p upregulation in exosomes promoted cell differentiation of NSCs. Furthermore, it can sensitized the AMPK signaling pathway. Following deprivation/reperfusion of oxygen-glucose, the differentiation of NSCs was restored, and exosomes significantly reduced cell apoptosis. MiR-9a-5p exosomes reduced the blood-brain barrier permeability and the infarct volume of rats with ischemic stroke in vivo. Neural cell apoptosis was reduced, thus indicating that miR-9a-5p could inhibit the cell apoptosis in vivo. AMPK activation was induced and increased in the MACO/R rat with miR-9a-5p exosomes. MiR-9a-5p exosomes could promote AMPK phosphorylation, increase NSC survival and enhance cell differentiation; this could inhibit the progression of ischemic stroke by maintaining an adequate number of neural cells and promoting endogenous NSC differentiation.