间质干细胞exosome转运14-3-3ζ抗肝纤维化的作用及机制

肝纤维化治疗目前尚缺乏理想的方法，间质干细胞（MSCs）在肝纤维化治疗中的作用越来越引起人们的重视。我们发现脐带MSCs分泌的外泌体（MSC-exosome）具有抗肝纤维化功能，然而作用机制并不清楚。预研究表明14-3-3ζ蛋白可能是MSC-exosome中抗肝纤维化的重要活性分子，且有研究发现14-3-3ζ可阻滞YAP入核，YAP核定位与肝纤维化胶原合成密切相关。基于前期研究和生物信息学分析，我们提出假说：在肝肌成纤维细胞中，MSC-exosome转运的14-3-3ζ通过抑制YAP入核下调LOXL2表达，降低胶原合成。本项目拟采用Ch-IP、Co-IP、双荧光素酶报告基因等技术揭示MSC-exosome转运14-3-3ζ抗肝纤维化的机制，并建立以MSC-exosome为载体过表达14-3-3ζ抗肝纤维化的方法，为MSC-exosome抗肝纤维化提供依据，为肝纤维化治疗提供新的策略。

There is still no ideal antifibrotic agent available and mesenchymal stem cells (MSCs) transplantation has recently gained increasing attention in liver fibrosis. We found that MSCs derived exosomes (MSC-exosome), an active component secreted by MSCs, could ameliorate carbon tetrachloride induced liver fibrosis in mice. However, the mechanisms for this amelioration remain unknown. Our preliminary study suggested that MSC-exosome exert antifibrotic effect through exosome mediated 14-3-3ζtransfer to myofibroblast (MFB). Previous studies have demonstrated that 14-3-3ζ can reduce YAP nuclear localization and YAP plays a key role in collagen synthesis of MFB. Based on these results and analysis of bioinformatics, we hypothesize that MSC-exosome derived 14-3-3ζ can suppress LOXL2 expression through inhibition of YAP nuclear localization, and thus decrease collagen synthesis and deposition in liver fibrosis. We will confirm the above hypothesis using experiments in vitro and in vivo to explore the role and mechanism of 14-3-3ζ from MSC-exosome in liver fibrosis. Then 14-3-3ζ overexpressed MSC-exosome will be produced and developed as a new strategy for treatment of liver fibrosis, which might provide evidence for MSC-exosome based antifibrotic therapy and a new therapeutic agent for liver fibrosis.