MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat.
MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat.
复制标题
间充质干细胞衍生的外泌体通过小胶质细胞/巨噬细胞促进大鼠创伤性脑损伤的恢复
DOI：
10.18632/aging.103692
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发表时间：
2020-09-23
期刊：
影响因子：
--
通讯作者：
Zhao RC
中科院分区：
文献类型：
--
作者：
Chen Y;Li J;Ma B;Li N;Wang S;Sun Z;Xue C;Han Q;Wei J;Zhao RC
创伤性脑损伤(TBI)是全世界年轻人发病和死亡的主要原因。目前尚无有效的临床治疗方法，但骨髓间充质干细胞来源的外切体已显示出良好的治疗效果。在这项研究中，我们进行了脑室内微量注射人脂肪间充质干细胞(HADSC)来源的外切体(hADSC-ex)在体重下降诱导的脑损伤大鼠模型中。我们发现，hADSC-ex可促进脑创伤大鼠功能恢复，抑制神经炎症，减少神经元凋亡，增加神经再生。HADSC-EX的疗效与hADSC相当。体内连续成像显示，dir标记的hADSC-ex在病变区域聚集增加。脑冠状切片和原代混合培养神经细胞的免疫荧光染色显示，CM-DiI标记的hADSC-ex与小胶质/巨噬细胞有明显重叠，表明hADSC-ex主要被小胶质/巨噬细胞摄取。在脂多糖诱导的炎症模型中，hADSC-ex通过抑制核因子κB和P38丝裂原活化蛋白激酶信号而抑制小胶质细胞/巨噬细胞的激活。这些数据表明，hADSC-EX特异性地进入小胶质细胞/巨噬细胞，并在脑损伤时抑制其激活，从而抑制炎症，促进功能恢复。它们也为hADSC-ex的细胞靶向、摄取和迁移提供了新的见解，并为中枢神经系统疾病的新治疗策略提供了理论基础。
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young individuals worldwide. There is currently no effective clinical treatment for TBI, but mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects. In this study, we performed intracerebroventricular microinjection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-ex) in a weight-drop-induced TBI rat model. We found that hADSC-ex promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis in TBI rats. The therapeutic effects of hADSC-ex were comparable to those of hADSC. Sequential in vivo imaging revealed increasing aggregation of DiR-labeled hADSC-ex in the lesion area. Immunofluorescent staining of coronal brain sections and primary mixed neural cell cultures revealed distinct overlap between CM-DiI-labeled hADSC-ex and microglia/macrophages, indicating that hADSC-ex were mainly taken up by microglia/macrophages. In a lipopolysaccharide-induced inflammatory model, hADSC-ex suppressed microglia/macrophage activation by inhibiting nuclear factor κB and P38 mitogen-activated protein kinase signaling. These data suggest that hADSC-ex specifically enter microglia/macrophages and suppress their activation during brain injury, thereby inhibiting inflammation and facilitating functional recovery. They also offer new insight into the cellular targeting, uptake and migration of hADSC-ex, and provide a theoretical basis for new therapeutic strategies for central nervous system diseases.
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作者：
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