Extracellular vesicles derived from inflammatory-educated stem cells reverse brain inflammation-implication of miRNAs
Extracellular vesicles derived from inflammatory-educated stem cells reverse brain inflammation-implication of miRNAs
复制标题
来自炎症教育干细胞的细胞外小泡逆转脑炎症--miRNAs的意义
DOI：
10.1016/j.ymthe.2021.08.008
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发表时间：
2022-01-05
影响因子：
12.4
通讯作者：
Mohapatra, Subhra
中科院分区：
文献类型：
--
作者：
Markoutsa, Eleni;Mayilsamy, Karthick;Mohapatra, Subhra
炎症在与年龄有关的疾病的发展中起着关键作用。在阿尔茨海默病中，神经元细胞死亡归因于触发小胶质细胞激活的淀粉样蛋白低聚物。由于干细胞的旁分泌活性和对炎症环境的反应能力，干细胞已经显示出治疗炎症性疾病的希望。然而，干细胞促进神经系统恢复的机制尚不清楚。为了阐明这些机制，我们首先用脂多糖或淀粉样蛋白激活的小胶质细胞分泌组诱导干细胞。然后，我们比较了引物干细胞和非引物干细胞分泌的细胞外囊泡（EVs）的免疫调节作用。我们的研究结果表明，与非启动细胞相比，来自启动细胞的电动汽车在抑制小胶质细胞和星形胶质细胞激活、淀粉样蛋白沉积、脱髓鞘、记忆丧失以及运动和焦虑样行为功能障碍方面更有效。MicroRNA （miRNA）分析显示，至少19种miRNA在引物干细胞ev中上调。鉴定出miRNA靶点，通过KEGG通路分析发现，过表达的miRNA靶向toll样受体-4 （TLR4）信号通路上的关键基因。总的来说，我们的研究结果表明，激活小胶质细胞分泌组的间充质干细胞（MSCs）导致ev释放具有增强免疫调节潜力的mirna，能够对抗神经炎症。
Inflammation plays a key role in the development of age-related diseases. In Alzheimer's disease, neuronal cell death is attributed to amyloidbeta oligomers that trigger microglial activation. Stem cells have shown promise as therapies for inflammatory diseases-because of their paracrine activity combined with their ability to respond to the inflammatory environment. However, the mechanisms underlying stem cell-promoted neurological recovery are poorly understood. To elucidate these mechanisms, we first primed stem cells with the secretome of lipopolysaccharide- or amyloidbeta-activated microglia. Then, we compared the immunomodulatory effects of extracellular vesicles (EVs) secreted from primed and nonprimed stem cells. Our results demonstrate that EVs from primed cells are more effective in inhibiting microglia and astrocyte activation, amyloid deposition, demyelination, memory loss and motor and anxiety-like behavioral dysfunction, compared to EVs from non-primed cells. MicroRNA (miRNA) profiling revealed the upregulation of at least 19 miRNAs on primed-stem cell EVs. The miRNA targets were identified, and KEGG pathway analysis showed that the overexpressed miRNAs target key genes on the toll-like receptor-4 (TLR4) signaling pathway. Overall, our results demonstrate that priming mesenchymal stem cells (MSCs) with the secretome of activated microglia results in the release of miRNAs from EVs with enhanced immune regulatory potential able to fight neuro-inflammation.