MSC-PD-L1调节肝移植后的肝脏微环境和损伤修复的机制研究

肝移植作为治疗终末期肝病的重要技术，为了保护移植的肝组织不被人体免疫系统排斥，患者需要终身服用抗排斥药物且副作用较大。我们希望利用间充质干细胞可以靶向迁移到炎症组织的特性，使其携带免疫抑制因子PD-L1用于治疗肝移植后的排斥反应，抑制淋巴细胞的功能和增殖，从而诱导免疫耐受的产生。同时MSCs具有向肝样细胞分化的特性，可以参与肝移植后的损伤修复过程，且具有免疫抑制效应。通过慢病毒转染系统或流式分选技术构建或筛选高表达PD-L1的MSCs，摸索其向肝样细胞分化条件；利用荧光标记和活体成像技术检测其是否能向肝移植特定部位趋化，实现器官特异性的治疗作用；通过对肝功能的检测，看MSC-PD-L1对肝移植是否具有损伤修复的作用；同时对进行MSC-PD-L1治疗前后肝脏免疫微环境的改变进行研究。这对于研发肝移植后具有靶向性的毒副作用较低的免疫抑制药物，减免非特异性免疫反应提供新的思路。

Liver transplantation is a well-recognized treatment for selected patients with non-resectable hepatocellular carcinoma (HCC), offering radical resection of HCC tumors and cure of the underlying disease with liver replacement. Lifelong pharmacological immunosuppression can achieve reasonable survival of liver grafts and patients; however, the acute and long-term side effects are significant. In this study, we utilize mesenchymal stem cells (MSCs) to deliver with PD-L1 to reduce the risk of rejection reaction. MSCs also possess a hepatocyte differentiation potential, which benefits for the injury repair after liver transplantation. In certain condition, the immunosuppression role of MSCs augments liver regeneration, reduces hepatic ischemia-reperfusion injury, and controls liver transplant rejection. After establishing the MSC-PD-L1 cell lines, we will explore the hepatocyte differentiation condition in vitro and in vivo. Further, MSC-PD-L1 targeted towards the liver transplantation site should be studied by in vivo imaging system and fluorescence labeling. Through the detection of liver function index, we will detect if MSC-PD-L1 could participate into the injury repair after liver transplantation. What’s more, the influence of MSC-PD-L1 on the immune microenvironment of liver should be investigated. Through this proposed study, we wish that MSC-PD-L1 might be valuable as immunomodulatory cell therapy for reducing immunity rejection after liver transplantation.