Neural Stem Cell-Derived Exosomes-Transmitted miR-31-5p Promote Functional Recovery of Spinal Cord Injury by Shifting Astrocytes A1/A2 Polarization.

Spinal cord injury (SCI) causes irreversible motor dysfunction, with reactive astrocytes contributing significantly to the secondary injury cascade. Neuronal stem cell (NSC)-derived exosomes have recently emerged as therapeutic carriers for functional microRNAs (miRNAs) in the central nervous system (CNS), yet their regulatory effects on astrocyte phenotypes in SCI remain unclear. We utilized in vivo and in vitro models of SCI to evaluate the therapeutic potential of NSC-derived exosomes. Microarray profiling was performed to identify exosomal miRNAs, followed by mechanistic validation using bioinformatics, RNA immunoprecipitation (RIP), luciferase reporter assays, and Western blotting. Functional outcomes were assessed by behavioral tests and rescue experiments in SCI mice. NSC-derived exosomes significantly enhanced motor recovery after SCI by shifting astrocytes from the A1-reactive phenotype to the neuroprotective A2-like properties. miR-31-5p was identified as the most enriched miRNA in exosomes and was found to directly target interleukin-34 (Il34), thereby downregulating the Il34/Stat3 signaling axis in astrocytes. Rescue assays confirmed that miR-31-5p-mediated suppression of Il34/Stat3 facilitates astrocytic phenotypic modulation and neurorepair. Our findings uncover a novel mechanism by which exosomal miR-31-5p modulates astrocyte phenotypes via the Il34/Stat3 pathway, highlighting its therapeutic potential as a miRNA-based intervention for promoting functional recovery after SCI.