Olfactory Mucosa Mesenchymal Stem Cell-Derived Exosomal lncRNA RMRP Regulates Glial Metabolic Reprogramming to Promote Axonal Regeneration After Spinal Cord Injury by Inhibiting WTAP-Mediated p53 m6A.

Glial metabolic reprogramming is essential for axonal regeneration post-spinal cord injury (SCI). While olfactory mucosa mesenchymal stem cell-derived exosomal lncRNA RMRP (OM-MSC-exo-RMRP) exhibits therapeutic potential for SCI, its involvement in glial metabolic reprogramming requires elucidation. OM-MSC-derived exosomes (OM-MSC-exos) were extracted and identified. Astrocytes (CTX-TNA2) were stimulated with TNF-α, treated with OM-MSC-exos, and co-cultured with dorsal root ganglion neuron (DRGns) to model glia-neuron interactions. DRGn axonal regeneration was assessed using immunofluorescence staining and western blotting. Astrocyte metabolism was assessed by detecting ECAR, OCR, glucose consumption, lactate production, and LDH activity. Molecular interactions among RMRP, WTAP, and p53 were determined by qPCR, western blotting, RNA immunoprecipitation, MeRIP-qPCR, and actinomycin D assays. A SCI mouse model was built and administered OM-MSC-exos, followed by histopathological evaluations using H&E, Nissl staining, and BMS scoring. RMRP was enriched in OM-MSC-exos and down-regulated in TNF-α-stimulated astrocytes. OM-MSC-exo treatment elevated RMRP expression, ECAR, glucose consumption, lactate production, LDH activity, decreased OCR in TNF-α-stimulated astrocytes, and promoted axonal regeneration. However, these effects were abolished when RMRP was down-regulated in OM-MSC-exos. Mechanistically, RMRP bound to WTAP in astrocytes, reducing WTAP expression and subsequent m6A of p53 mRNA, thereby destabilizing p53. WTAP or p53 overexpression could reverse RMRP overexpression-induced astrocyte metabolic reprogramming and DRGn axonal regeneration. In vivo assays indicated that OM-MSC-exo treatment promoted motor function, glycolysis, and axonal regeneration after SCI by transferring RMRP, with decreased WTAP and p53 expressions. OM-MSC-exo-RMRP mediates metabolic reprogramming to promote post-SCI axonal regeneration via inhibiting WTAP-mediated p53 m6A.