间充质干细胞通过外泌体传递microRNA-10a于单核细胞以缓解脓毒症的机制研究

The mortality for sepsis remains high despite the recent advances in vaccines, antibiotics, and intensive care. Our group was the first to document that mesenchymal stem cells (MSCs) attenuate the LPS-induced inflammatory responses in a mouse model. Recent studies have demonstrated that MSCs are able to release miRNAs via exosomes for intercellular communications. Preliminary studies from our group showed high expression of miR-10a in exosomes from MSCs. Also, miR-10a levels were decreased in monocytes treated with LPS and returned to basal levels when monocytes were pre-cocultured with MSCs. We hypothesize that MSCs transfer miR-10a containing exosomes to monocytes and suppress monocyte activation. Second, MSCs downregulate MAP4K4-TAK1-MKK4-JNK pathway in monocytes via miR-10a. Finally, miR-10a mediates the beneficial effects of MSCs in sepsis in vivo. There are no reports for similar studies in the literature. Our study may provide new insights into the mechanisms of MSCs on sepsis and may also reveal evidences that MSCs and their exosomes might be potential therapeutic tools for treating sepsis.

尽管疫苗，抗感染和重症监护技术在近年取得了较大的进步，脓毒症的病死率仍居高不下。我们团队最先在国际上发现间充质干细胞(MSCs)能够改善小鼠 LPS 诱导的炎症反应。近期文献报道MSCs可通过外泌体传递miRNA参与胞间通讯。前期实验中我们已证实MSCs的外泌体富含miR-10a;而且，miR-10a在LPS刺激的单核细胞中低表达，而这种现象在与MSCs共培养的单核细胞中被逆转。本课题假设①MSCs分泌的外泌体传递 miR-10a 于单核细胞并抑制LPS对单核细胞的激活作用；②同时，MSCs通过miR-10a负调节单核细胞MAP4K4-TAK1-MKK4-JNK信号通路；③最后，miR-10a介导MSCs在体内缓解脓毒症的作用。以上假设均为全新思维，本课题有助于阐明MSCs改善脓毒症的分子机制，为应用MSCs或其外泌体治疗脓毒症提供依据。

尽管近年来疫苗、抗生素和重症监护取得了较大进步，脓毒症（sepsis）的病死率仍居高不下。许多研究发现间充质干细胞（MSCs）可减轻脓毒症并降低死亡率。MSCs可通过胞外囊泡传递miRNA参与细胞间通讯。本课题（间充质干细胞通过外泌体传递microRNA-10a于单核细胞以缓解脓毒症的机制研究，81772122）研究发现脓毒症患者外周血单个核细胞中miR-10a表达降低，与疾病的严重程度呈负相关；miR-10a可能是脓毒症的生物标记物。进一步探讨间充质干细胞在急性肺损伤中的作用机制，发现间充质干细胞来源的胞外囊泡（MSC-EVs）传递miR-27a-3p于巨噬细胞以减轻急性肺损伤；而老年和年轻MSC-EVs对减轻急性肺损伤和调控巨噬细胞极化发挥不同作用。