Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
Department of Neurology, Renji Hospital of Shanghai Jiao Tong University, No. 160 Pujian Rd, Shanghai 200127, China.
Theranostics. 2021 Jan 1;11(3):1232-1248. doi: 10.7150/thno.48761. eCollection 2021.
Glial scars present a major obstacle for neuronal regeneration after stroke. Thus, approaches to promote their degradation and inhibit their formation are beneficial for stroke recovery. The interaction of microglia and astrocytes is known to be involved in glial scar formation after stroke; however, how microglia affect glial scar formation remains unclear. Mice were treated daily with M2 microglial small extracellular vesicles through tail intravenous injections from day 1 to day 7 after middle cerebral artery occlusion. Glial scar, infarct volume, neurological score were detected after ischemia. microRNA and related protein were examined in peri-infarct areas of the brain following ischemia. M2 microglial small extracellular vesicles reduced glial scar formation and promoted recovery after stroke and were enriched in miR-124. Furthermore, M2 microglial small extracellular vesicle treatment decreased the expression of the astrocyte proliferation gene signal transducer and activator of transcription 3, one of the targets of miR-124, and glial fibrillary acidic protein and inhibited astrocyte proliferation both and . It also decreased Notch 1 expression and increased Sox2 expression in astrocytes, which suggested that astrocytes had transformed into neuronal progenitor cells. Finally, miR-124 knockdown in M2 microglial small extracellular vesicles blocked their effects on glial scars and stroke recovery. Our results showed, for the first time, that microglia regulate glial scar formation small extracellular vesicles, indicating that M2 microglial small extracellular vesicles could represent a new therapeutic approach for stroke.
胶质瘢痕是中风后神经元再生的主要障碍。因此，促进其降解和抑制其形成的方法有利于中风的恢复。已知小胶质细胞和星形胶质细胞的相互作用参与了中风后胶质瘢痕的形成；然而，小胶质细胞如何影响胶质瘢痕的形成尚不清楚。 从小鼠大脑中动脉闭塞后第 1 天到第 7 天，每天通过尾静脉注射 M2 小胶质细胞小细胞外囊泡进行治疗。缺血后检测胶质瘢痕、梗死体积、神经评分。 缺血后检测脑梗死区周围的 microRNA 和相关蛋白。 M2 小胶质细胞小细胞外囊泡减少了中风后的胶质瘢痕形成和恢复，并且富含 miR-124。此外，M2 小胶质细胞小细胞外囊泡处理降低了星形胶质细胞增殖基因信号转导和转录激活因子 3 的表达，miR-124 的一个靶基因，以及胶质纤维酸性蛋白，并抑制星形胶质细胞增殖和。它还降低了星形胶质细胞中的 Notch1 表达并增加了 Sox2 表达，这表明星形胶质细胞已转化为神经元祖细胞。最后，miR-124 在 M2 小胶质细胞小细胞外囊泡中的敲低阻断了它们对胶质瘢痕和中风恢复的影响。 我们的研究结果首次表明，小胶质细胞调节胶质瘢痕形成小细胞外囊泡，表明 M2 小胶质细胞小细胞外囊泡可能代表中风的一种新的治疗方法。
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