间充质干细胞（MSCs）在维持机体内环境稳定，促进组织修复中占重要地位。募集至病损部位MSCs与损伤微环境存在密切作用，决定疾病进展和转归。我们发现炎症赋予MSCs免疫调控特性，炎症动态变化决定MSCs免疫抑制作用可塑性。依据MSCs免疫调节可塑性，不同炎症状态下MSCs发挥不同的治疗肝损伤作用。究竟免疫微环境如何调控MSCs的免疫抑制能力和调节组织修复仍不清楚。因此，我们提出假设炎症与MSCs的互作在决定免疫病理状态和组织修复中发挥重要作用。围绕这一假设，以肝硬化为模型，本项目拟探讨1）内源性MSCs塑造肝硬化病理微环境的机制；2）MSCs对免疫反应的调节在肝硬化致病及转归中的作用；3）炎症对MSCs介导组织修复的影响在肝硬化中的作用及机制；4）探索基于MSCs与免疫相互作用形成的肝硬化治疗新策略。研究将以MSCs与免疫为视角，多层次分析肝硬化的致病机制及转归调节，形成肝硬化治疗新手段。

Mesenchymal stem cells (MSCs) residing in various tissues play pivotal roles in maintaining cellular homoeostasis and promoting tissue repair. Exogenously administrated MSCs migrate to damages tissue sites, whereby they participate in tissue reparative processes via their crosstalk with inflammation, thus determining the progression and prognosis of various diseases. We have found that the immunosuppressive properties of MSCs is not constitutive, instead, it is initiated by inflammatory cytokines, such as those in the inflammatory microenvironment. More importantly, the amounts and kinds of inflammatory cytokines that change during the progression of inflammatory diseases variably influence the immunoregulatory properties of MSCs. Based on such plasticity of immunoregulatory properties of MSCs, our investigations have revealed that MSCs under different inflammatory stimulation can enhance or block their therapeutic effects on liver injuries. However, how inflammatory microenvironment modulates immunoregulation and reparative function of MSCs remains unclear. Hence, we hypothesize that the interaction between MSCs and inflammation plays important roles in regulating the immunopathological status and tissue repair process. We propose 4 specific aims to test this hypothesis. Based on our established liver cirrhosis models, we will determine 1) the mechanisms of tissue-resident MSCs in orchestrating the pathological microenvironment during liver cirrhosis; 2) the role of MSC-mediated immunoregulation in the pathogenesis and prognosis of liver cirrhosis; 3) the function of inflammation induced MSC-based tissue repair in the pathogenesis and prognosis of liver cirrhosis; 4) the development of potential MSC-based liver cirrhosis therapy. We believe that the completion of this study will provide not only critical information for understanding of the formation and regulation of cirrhotic microenvironment, but also for designing new strategies to treat liver cirrhosis.