Exosomal lncRNA RMRP-shuttled by Olfactory Mucosa-Mesenchymal Stem Cells Suppresses Microglial Pyroptosis to Improve Spinal Cord Injury via EIF4A3/SIRT1.

Microglial pyroptosis significantly influences the pathological process and functional recovery after spinal cord injury (SCI). Olfactory mucosal mesenchymal stem cells (OM-MSCs) have shown remarkable therapeutic effects in SCI due to their neural substitution potential and paracrine mechanism. Therefore, the purpose of this study was to investigate the function and mechanism of OM-MSCs-derived exosomes (Exo) in regulating microglial pyroptosis after SCI. OM-MSCs and their secreted Exo were extracted and identified correspondingly. Microglia cells (HMC3) were stimulated by lipopolysaccharide (LPS) and co-cultured with Exo; the cell viability and pyroptosis of HMC3 cells were validated by CCK-8 and flow cytometry analysis. The inflammatory cytokines and pyroptosis-related proteins were measured by ELISA and western blot. Molecular interactions were verified by RNA immunoprecipitation and RNA pull-down. The SCI mouse model was constructed and administered with Exo, and then the histopathological features were detected using H&E, Nissl staining, and BMS score. lncRNA RMRP was enriched in OM-MSCs-Exo and downregulated in LPS-induced HMC3 cells. OM-MSCs-Exo administration markedly elevated lncRNA RMRP expression and repressed microglial pyroptosis in LPS-induced HMC3 cells, while these effects were diminished when lncRNA RMRP was depleted in OM-MSCs-Exo. Mechanistically, lncRNA RMRP maintained SIRT1 mRNA stability by recruiting EIF4A3. Overexpression of SIRT1 could rescue lncRNA RMRP knockdown-mediated microglia pyroptosis. In vivo data further supported that OM-MSCs-Exo administration relieves pyroptosis and nerve damage after SCI by carrying lncRNA RMRP. Our data suggested that exosomal lncRNA RMRP mitigated microglia pyroptosis and promoted motor function recovery after SCI by regulating the EIF4A3/SIRT1 axis.