Gu Jun, Wu Jingyi, Wang Chunming, Xu Zhenwei, Jin Zhengshuai, Yan Donghua, Chen Sheng
The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, China.
Aging (Albany NY). 2024 Mar 11;16(6):5184-5206. doi: 10.18632/aging.205638.
Spinal cord injury (SCI) results in a diverse range of disabilities and lacks effective treatment options. In recent years, exosomes derived from bone mesenchymal stem cells (BMSCs) have emerged as a promising cell-free therapeutic approach for treating ischemic brain injury and other inflammatory conditions. Macrophage/microglial pyroptosis has been identified as a contributing factor to neuroinflammation following SCI. The therapeutic potential of BMSC-derived exosomes in macrophage/microglia pyroptosis-induced neuroinflammation, however, has to be determined. Our findings demonstrate that exosomes derived from BMSCs can enhance motor function recovery and mitigate neuroinflammation subsequent to SCI by upregulating the expression of autophagy-related proteins and inhibiting the activation of NLRP3 inflammasomes in macrophage/microglia. Moreover, miR-21a-5p is markedly increased in BMSCs-derived exosomes, and knocking down miR-21a-5p in BMSCs-derived exosomes eliminates the beneficial effects of administration; upregulation of miR-21a-5p in BMSCs-derived exosomes enhances the beneficial effects of administration. Mechanistically, miR-21a-5p positively regulates the autophagy of macrophage/microglia by reducing PELI1 expression, which in turn inhibits their pyroptosis. This research provides novel evidence that exosomes derived from BMSCs can effectively suppress macrophage/microglia pyroptosis through the miR-21a-5p/PELI1 axis-mediated autophagy pathway, ultimately facilitating functional restoration following SCI. In particular, our constructed miR-21a-5p overexpression exosomes greatly improved the efficacy of BMSCs-derived exosomes in treating spinal cord injury. These results establish a foundation for the prospective utilization of exosomes derived from BMSCs as a novel biological intervention for spinal cord injury.
脊髓损伤（SCI）会导致多种残疾，且缺乏有效的治疗选择。近年来，源自骨髓间充质干细胞（BMSCs）的外泌体已成为一种有前景的无细胞治疗方法，用于治疗缺血性脑损伤和其他炎症性疾病。巨噬细胞/小胶质细胞焦亡已被确定为SCI后神经炎症的一个促成因素。然而，BMSC来源的外泌体在巨噬细胞/小胶质细胞焦亡诱导的神经炎症中的治疗潜力尚待确定。我们的研究结果表明，BMSCs来源的外泌体可通过上调自噬相关蛋白的表达并抑制巨噬细胞/小胶质细胞中NLRP3炎性小体的激活，来增强SCI后的运动功能恢复并减轻神经炎症。此外，miR-21a-5p在BMSCs来源的外泌体中显著增加，敲低BMSCs来源外泌体中的miR-21a-5p会消除给药的有益效果；上调BMSCs来源外泌体中的miR-21a-5p可增强给药的有益效果。从机制上讲，miR-21a-5p通过降低PELI1表达来正向调节巨噬细胞/小胶质细胞的自噬，进而抑制其焦亡。本研究提供了新的证据，表明BMSCs来源的外泌体可通过miR-21a-5p/PELI1轴介导的自噬途径有效抑制巨噬细胞/小胶质细胞焦亡，最终促进SCI后的功能恢复。特别是，我们构建的miR-21a-5p过表达外泌体大大提高了BMSCs来源外泌体治疗脊髓损伤的疗效。这些结果为将BMSCs来源的外泌体作为脊髓损伤的新型生物干预措施的前瞻性应用奠定了基础。
