Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p
Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p
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人脐带间充质干细胞来源的外切体通过miR-455-3p改善IL-6诱导的急性肝损伤
DOI：
10.1186/s13287-020-1550-0
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发表时间：
2020-01-23
影响因子：
7.5
通讯作者：
Bu, Hong
中科院分区：
文献类型：
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作者：
Shao, Mingyang;Xu, Qing;Bu, Hong
背景我们之前使用毒素诱导的非人灵长类动物急性肝衰竭（ALF）模型报道，人脐带间充质干细胞（hUC-MSC）的外周输注强烈抑制循环单核细胞的活化和白细胞介素6（IL-6）的产生，从而破坏细胞因子风暴的发展并改善猴子的预后。 MSCs被认为在不同的压力下通过适应性地产生特定因子来发挥治疗作用，这促使我们研究hUC-MSCs响应高血清水平的IL-6而产生的因子，IL-6在启动和加速ALF中起着关键作用。方法我们用IL-6刺激hUC-MSC，并对hUC-MSC衍生的外泌体进行深度测序。筛选了外泌体中具有抑制IL-6相关信号通路潜力的miRNA，并在小鼠炎症性肝损伤模型中测试了最可能的miRNA之一的作用。结果我们确定，hUC-MSCs 在 IL-6 刺激下大量产生 miR-455-3p，该 miR-455-3p 通过外泌体分泌，并可能靶向 PI3K 信号传导。富含 miR-455-3p 的外泌体可以在体内和体外抑制脂多糖（LPS）攻击的巨噬细胞的活化和细胞因子的产生。在化学性肝损伤小鼠模型中，miR-455-3p的强制表达可以减轻巨噬细胞浸润和局部肝脏损伤，并降低血清炎症因子水平，从而改善肝脏组织学和全身疾病。结论 来自 hUC-MSC 的富含 miR-455-3p 的外泌体是治疗急性炎症性肝损伤的一种有前途的疗法。
Background Using a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys. MSCs are considered to play a therapeutic role under different stresses by adaptively producing specific factors, prompting us to investigate the factors that hUC-MSCs produce in response to high serum levels of IL-6, which plays a critical role in initiating and accelerating ALF. Methods We stimulated hUC-MSCs with IL-6, and the hUC-MSC-derived exosomes were deeply sequenced. The miRNAs in the exosomes that have potential to suppress IL-6-associated signaling pathway were screened, and the role of one of the most possible miRNAs was tested in the mouse model of inflammatory liver injury. Result We determined that miR-455-3p, which is secreted through exosomes and potentially targets PI3K signaling, was highly produced by hUC-MSCs with IL-6 stimulation. The miR-455-3p-enriched exosomes could inhibit the activation and cytokine production of macrophages challenged with lipopolysaccharide (LPS) both in vivo and in vitro. In a chemical liver injury mouse model, enforced expression of miR-455-3p could attenuate macrophage infiltration and local liver damage and reduce the serum levels of inflammatory factors, thereby improving liver histology and systemic disorder. Conclusions miR-455-3p-enriched exosomes derived from hUC-MSCs are a promising therapy for acute inflammatory liver injury.