hUCMSC源胞外囊泡抑制IL-13介导的HSC活化减轻血吸虫性肝脏病理及机制

Schistosomiasis is an important zoonotic parasitic disease that causes serious harms to humans and animals. The major pathological damage occurring in schistosomiasis is attributable to the granulomatous inflammatory response and liver fibrosis induced by schistosome eggs. At present, no effective drug therapy is available for the fibrosis treatment. Our pre-experiment showed that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-EVs) can inhibit liver fibrosis in mice infected with schistosomiasis, reduce the level of IL-13 in infected mice, and inhibit the activation of IL-13-induced hepatic stellate cells (HSC). There is abundant miR-30a in hUCMSC-EVs. It has been discovered that miR-30a binds to the 3'UTR of IL-13Rα1 by the software prediction. We speculate that hUCMSC-EVs may regulate IL-13 signaling pathway by transmitting miR-30a to HSC and inhibiting the expression of IL-13Rα1. We will explore the relationship between miR-30a and IL-13Rα1 in HSC cells using gene interference, luciferase reporter. And we will explore the function of miR-30a in IL-13-mediated HSC activation and in hUCMSC-EVs. Our study will provide a new target for the treatment of liver fibrosis and type II immune diseases.

血吸虫病是一种威胁人类健康的人兽共患病，主要病变为虫卵引发的肝脏肉芽肿和纤维化，目前缺乏有效药物用于驱虫后肝脏纤维化治疗。我们预实验显示人脐带间充质干细胞源胞外囊泡（hUCMSC-EVs）可以抑制血吸虫感染小鼠肝脏纤维化，降低感染小鼠体内IL-13含量，抑制IL-13诱导的肝脏星状细胞（HSC）活化，hUCMSC-EVs中含有高丰度miR-30a，软件预测发现miR-30a可以和IL-13Rα1的3'UTR结合。我们推测hUCMSC-EVs可能通过传递miR-30a至HSC，抑制IL-13Rα1表达来调控IL-13信号通路。本项目拟应用基因干扰、荧光素酶报告基因技术探讨miR-30a与IL-13Rα1关系，免疫印迹、EDU等技术观察miR-30a在IL-13介导的HSC活化中的作用及miR-30a在hUCMSC-EVs中的作用，为肝脏纤维化及II型免疫性疾病治疗提供新的靶点。

血吸虫病是一种威胁人类健康的人兽共患病，主要病变为虫卵引发的肝脏肉芽肿和纤维化，目前缺乏有效药物用于驱虫后肝脏纤维化治疗。本项目旨在探讨人脐带间充质干细胞源胞外囊泡（hUCMSC-EVs）对血吸虫性肝损伤的治疗作用与机制，并探究hUCMSC-EVs对其它II型免疫性疾病，如过敏性哮喘的影响。我们发现1）hUCMSC-EVs可延长血吸虫感染小鼠的生存期，缓解肝脏肉芽肿和纤维化进程，且抑制肝脏内II型细胞因子（如IL-4）表达和星状细胞（HSC）活化；体外细胞实验证实hUCMSC-EVs可降低HSC的增殖和活性，抑制IL-13诱导的HSC活化，其机制是hUCMSC-EVs通过传递miR-30a介导IL-13受体IL-13Rα1下调。2）hUCMSC-EVs—特别是乏氧环境下（5% O2）hUCMSC源EVs（Hypo-EVs），可显著减轻哮喘小鼠气道炎性细胞的浸润和气道重塑，降低肺泡灌洗液中II型细胞因子（如IL-4和IL-13）的含量，且下调肺脏内TGF-β1-Smad2/3信号；进一步研究发现乏氧环境可上调hUCMSC-EVs中miR-146a-5p水平，而敲减Hypo-EVs中miR-146a-5p水平显著削弱了Hypo-EVs对哮喘小鼠肺脏损伤的治疗作用。以上结果揭示了hUCSMC-EVs缓解血吸虫性肝损伤和减轻哮喘气道病理的作用和机制，为hUCMSC-EVs用于II型免疫性疾病的临床治疗奠定了实验基础，具有重要的科学意义和临床价值。