BACKGROUND Spinal cord injury (SCI) has a very disabling central nervous system impact but currently lacks effective treatment. Bone marrow-derived macrophages (BMDMs) are recruited to the injured area after SCI and participate in the regulation of functional recovery with microglia. Previous studies have shown that M2 microglia-derived small extracellular vesicles (SEVs) have neuroprotective effects, but the effects of M2 BMDM-derived sEVs (M2 BMDM-sEVs) have not been reported in SCI treatment. RESULTS In this study, we investigated the role of M2 BMDM-sEVs in vivo and in vitro for SCI treatment and its mechanism. Our results indicated that M2 BMDM-sEVs promoted functional recovery after SCI and reduced neuronal apoptosis in mice. In addition, M2 BMDM-sEVs targeted mammalian target of rapamycin (mTOR) to enhance the autophagy level of neurons and reduce apoptosis. MicroRNA-421-3P (miR-421-3p) can bind to the 3' untranslated region (3'UTR) of mTOR. MiR-421-3p mimics significantly reduced the activity of luciferase-mTOR 3'UTR constructs and increased autophagy. At the same time, tail vein injection of inhibitors of SEVs (Inh-sEVs), which were prepared by treatment with an miR-421-3p inhibitor, showed diminished protective autophagy of neuronal cells in vivo. CONCLUSIONS In conclusion, M2 BMDM-sEVs inhibited the mTOR autophagy pathway by transmitting miR-421-3p, which reduced neuronal apoptosis and promoted functional recovery after SCI, suggesting that M2 BMDM-sEVs may be a potential therapy for SCI.

中文翻译：

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来自M2骨髓巨噬细胞的MicroRNA-421-3p丰富的小细胞外囊泡通过抑制脊髓损伤中的mTOR来减弱细胞凋亡并促进运动功能恢复。

背景技术脊髓损伤（SCI）具有非常严重的中枢神经系统影响，但是目前缺乏有效的治疗方法。脊髓损伤后将骨髓来源的巨噬细胞（BMDM）募集到受伤区域，并参与小胶质细胞功能恢复的调节。先前的研究表明，M2小胶质细胞衍生的小细胞外囊泡（SEV）具有神经保护作用，但SCI治疗中尚未报道M2 BMDM衍生的sEV（M2 BMDM-sEV）的作用。结果在这项研究中，我们调查了M2 BMDM-sEVs在体内和体外对SCI治疗的作用及其机制。我们的结果表明，M2 BMDM-sEVs促进SCI后的功能恢复并减少小鼠的神经元凋亡。此外，M2 BMDM-sEVs靶向雷帕霉素（mTOR）的哺乳动物靶标，以增强神经元的自噬水平并减少细胞凋亡。MicroRNA-421-3P（miR-421-3p）可以与mTOR的3'非翻译区（3'UTR）结合。MiR-421-3p模拟物显着降低了萤光素酶-mTOR 3'UTR构建体的活性，并增加了自噬。同时，通过用miR-421-3p抑制剂治疗制备的SEV抑制剂（Inh-sEVs）的尾静脉注射显示体内神经元细胞的保护性自噬减少。结论综上所述，M2 BMDM-sEVs通过传递miR-421-3p抑制mTOR自噬途径，从而减少神经元凋亡并促进SCI后的功能恢复，提示M2 BMDM-sEVs可能是SCI的潜在疗法。mTOR的非翻译区（3'UTR）。MiR-421-3p模拟物显着降低了萤光素酶-mTOR 3'UTR构建体的活性，并增加了自噬。同时，通过用miR-421-3p抑制剂处理制备的SEV抑制剂（Inh-sEVs）的尾静脉注射显示体内神经元细胞的保护性自噬减少。结论综上所述，M2 BMDM-sEVs通过传递miR-421-3p抑制mTOR自噬途径，从而减少神经元凋亡并促进SCI后的功能恢复，提示M2 BMDM-sEVs可能是SCI的潜在疗法。mTOR的非翻译区（3'UTR）。MiR-421-3p模拟物显着降低了萤光素酶-mTOR 3'UTR构建体的活性，并增加了自噬。同时，通过用miR-421-3p抑制剂处理制备的SEV抑制剂（Inh-sEVs）的尾静脉注射显示体内神经元细胞的保护性自噬减少。结论综上所述，M2 BMDM-sEVs通过传递miR-421-3p抑制mTOR自噬途径，从而减少神经元凋亡并促进SCI后的功能恢复，提示M2 BMDM-sEVs可能是SCI的潜在疗法。通过用miR-421-3p抑制剂处理而制备的化合物显示出体内神经元细胞的保护性自噬减少。结论总之，M2 BMDM-sEVs通过传递miR-421-3p抑制mTOR自噬途径，从而减少SCI后的神经元凋亡并促进功能恢复，这表明M2 BMDM-sEVs可能是SCI的潜在疗法。通过用miR-421-3p抑制剂处理而制备的化合物显示出体内神经元细胞的保护性自噬减少。结论综上所述，M2 BMDM-sEVs通过传递miR-421-3p抑制mTOR自噬途径，从而减少神经元凋亡并促进SCI后的功能恢复，提示M2 BMDM-sEVs可能是SCI的潜在疗法。