Exosomal miR-128-3p reversed fibrinogen-mediated inhibition of oligodendrocyte progenitor cell differentiation and remyelination after cerebral ischemia

Abstract

Aims: To investigate the role of exosomal miR-128-3p in promoting fibrinogen-mediated inhibition of oligodendrocyte progenitor cell (OPC) differentiation and the therapeutic potential of exosomal miR-128-3p in cerebral ischemia. Methods: Mouse models of middle cerebral artery occlusion (MCAO) were established as described previously. MCAO was treated with fibrinogen and exosomes by stereotactically injecting into the left stratum. Mouse cortical OPCs were used for mRNA and miRNA sequencing analysis. Exosomes were isolated from neural stem cells (NSCs) of mice. Results: Fibrinogen deposition suppressed remyelination after MCAO and inhibited OPC differentiation by activating ACVR1, the bone morphogenetic protein (BMP) signaling type I receptor. In vitro, miR-sequencing and verification studies revealed that miR-128-3p is associated with BMP signaling mediated by ACVR1. Additionally, transfer of NSC-derived exosomal miR-128-3p to OPCs significantly increased myelin basic protein expression and inhibited BMP signaling. Furthermore, NSC-derived exosomal miR-128-3p protected against fibrinogen-induced demyelination related to BMP signaling, reduced the infarct volume, and improved neurological function after MCAO. Conclusions: Fibrinogen deposition inhibits remyelination after ischemic damage and NSC-derived exosomal miR-128-3p promotes OPC differentiation into OLs by suppressing BMP signaling, indicating that NSC-derived exosomal miR-128-3p represents a potential therapeutic target for ischemic stroke.