基于肝类器官模型探讨胎盘MSC外泌体miR-378c的抗纤维化作用及机制

间充质干细胞（MSC）外泌体具有潜在的抗纤维化作用，但机制未明。预实验基于肝类器官模型显示，胎盘MSC（Pd-MSC）外泌体可抑制纤维化表型；进一步测序发现miR-378c是外泌体中关键抗纤维化因子，可抑制类器官上皮间质转化（EMT）和肝星状细胞（HSC）活性；泛素化抑制剂可拮抗miR-378c靶基因SKP2对E-cadherin和P21/P27的调控作用。据此提出假说：Pd-MSC外泌体miR-378c通过靶向SKP2抑制肝细胞EMT和HSC活性，进而改善肝纤维化。本项目拟完成：基于类器官和动物模型，多指标验证Pd-MSC外泌体miR-378c的抗纤维化特性，并明确其对肝细胞EMT和HSC活性的调控作用；通过多因素表型/机制挽救实验共同探讨miR-378c靶向SKP2泛素化信号轴调控肝纤维化的分子机制。本研究将阐明Pd-MSC外泌体改善肝纤维化的分子机制，为肝纤维化治疗提供新的思路。

Previous studies have indicated the anti-fibrotic features of exosomes from mesenchymal stem cell (MSC). However, the underlying mechanisms remain unclear. Based on the liver organoid model, our previous work indicated the anti-fibrosis effects of the exosomes from placenta-derived MSC(Pd-MSC). Further miR-sequence found that miR-378c might be the key anti-fibrotic factor in the exosome, which inhibit the epithelial-mesenchymal transition (EMT) and the activity of hepatic stellate cell (HSC). In addition, the ubiquitylation inhibitor abrogated the regulatory effects of SKP2 (the target gene of miR-378c) on E-cadherin and P21/P27. Thus, we proposed the hypothesis that the exosomal miR-378c from Pd-MSC inhibited liver fibrosis via inhibiting EMT phenotype and activity of HSC by targeting SKP2. We aim to verify the anti-fibrosis function of exosomal miR-378c with multi-index and the regulatory effects on EMT of hepatocyte and HSC activation. In addition, we will conduct the multi-factor phenotype/ mechanism rescue assays to explore the underlying mechanism that miR-378c/SKP2-mediated ubiquitylation axis regulates the therapeutic function against liver fibrosis. The study will clarify the potential anti-fibrosis mechanism of exosome from Pd-MSC and provide a new theoretical basis for the therapy of liver fibrosis.