Exosomal miR-9-5p derived from BMSCs alleviates apoptosis, inflammation and endoplasmic reticulum stress in spinal cord injury by regulating the HDAC5/FGF2 axis

Abstract

Exosomes derived from human bone marrow mesenchymal stem cells (BMSCs) play potential protective roles in spinal cord injury (SCI). However, the underlying mechanisms remain not fully elucidated. Herein, we isolated exosomes from BMSCs, and exosome morphology and marker protein levels were identified by transmission electron microscopy (TEM) and Western blot, respectively. PC12 cells were treated with lipopolysaccharide (LPS) to construct an injury model, and then incubated with BMSCs-derived exosomes. We found that exosome incubation increased miR-9-5p expression, and inhibited apoptosis and the levels of inflammation cytokines and ER stress marker proteins. Moreover, histone deacetylase 5 (HDAC5) was identified as a target gene of miR-9-5p by dual-luciferase reporter gene assay. Exosomal miR-9-5p upregulated fibroblast growth factor 2 (FGF2) expression by inhibiting HDAC5-mediated FGF2 deacetylation. Then, it was observed that HDAC5 overexpression or FGF2 inhibition reversed the inhibitory effects of exosomal miR-9-5p on apoptosis, inflammation and ER stress in PC12 cells. Additionally, an SCI rat model was established and exosomes were injected for treatment. Exosomal miR-9-5p treatment alleviated locomotor ability, histopathological damage, neuronal apoptosis, inflammation and ER stress in SCI rats. In conclusion, our findings indicated that exosomal miR-9-5p derived from BMSCs promoted FGF2 expression by inhibiting HDAC5-mediated deacetylation, thus inhibiting LPS-induced apoptosis, inflammation, and ER stress in PC12 cells, and alleviating SCI in rat model. Our study may provide a therapeutic direction for SCI.

Keywords: BMSCs; ER stress; Exosomal miR-9-5p; FGF2; HDAC5; Spinal cord injury.