Wang Chuang, Zhang Jiangshan, Zeng Danting, Chen Pengcheng, Chen Weimin, Xia Ying
Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, P.R. China.
Department of Neurology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, P.R. China.
FASEB J. 2026 Jan 31;40(2):e71461. doi: 10.1096/fj.202502473R.
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 mA 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 mA.
神经胶质细胞代谢重编程对于脊髓损伤（SCI）后的轴突再生至关重要。虽然嗅黏膜间充质干细胞来源的外泌体长链非编码RNA RMRP（OM-MSC-exo-RMRP）对SCI具有治疗潜力，但其在神经胶质细胞代谢重编程中的作用尚需阐明。提取并鉴定了OM-MSC来源的外泌体（OM-MSC-exos）。用TNF-α刺激星形胶质细胞（CTX-TNA2），用OM-MSC-exos处理，并与背根神经节神经元（DRGns）共培养以模拟神经胶质-神经元相互作用。使用免疫荧光染色和蛋白质印迹法评估DRGn轴突再生。通过检测细胞外酸化率（ECAR）、氧消耗率（OCR）、葡萄糖消耗、乳酸产生和乳酸脱氢酶（LDH）活性来评估星形胶质细胞的代谢。通过定量聚合酶链反应（qPCR）、蛋白质印迹法、RNA免疫沉淀、甲基化RNA免疫沉淀测序-qPCR（MeRIP-qPCR）和放线菌素D试验确定RMRP、WTAP和p53之间的分子相互作用。建立SCI小鼠模型并给予OM-MSC-exos，随后使用苏木精-伊红（H&E）染色、尼氏染色和Basso小鼠运动评分（BMS）进行组织病理学评估。RMRP在OM-MSC-exos中富集，在TNF-α刺激的星形胶质细胞中下调。OM-MSC-exo处理可提高RMRP表达、ECAR、葡萄糖消耗、乳酸产生、LDH活性，降低TNF-α刺激的星形胶质细胞中的OCR，并促进轴突再生。然而，当OM-MSC-exos中的RMRP下调时，这些作用被消除。机制上，RMRP与星形胶质细胞中的WTAP结合，降低WTAP表达以及随后p53 mRNA的N6-甲基腺苷（mA）水平，从而使p53不稳定。WTAP或p53过表达可逆转RMRP过表达诱导的星形胶质细胞代谢重编程和DRGn轴突再生。体内试验表明，OM-MSC-exo处理通过转移RMRP促进SCI后的运动功能、糖酵解和轴突再生，同时降低WTAP和p53表达。OM-MSC-exo-RMRP通过抑制WTAP介导的p53 mA来介导代谢重编程，从而促进SCI后的轴突再生。
