间充质干细胞与免疫微环境的交互调控在肝硬化中的作用及机制

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.

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。

间充质干细胞（mesenchymal stem cells, MSCs）是一种具有多向分化潜能的组织干细胞。炎症因子是MSCs发挥重要免疫调节作用的决定性因素，而炎症状态（细胞因子水平及种类等）决定MSCs免疫调节状态的可塑性。不同炎症状态下，MSCs发挥不同的治疗作用。本项目以MSCs与免疫的相互作用为主线，重点研究MSCs在肝硬化病理进程中的作用及机制。通过研究发现，（1）与常规治疗组相比，MSCs输注可有效治疗肝硬化，而MSCs对肝硬化治疗的有效性与病人血清中炎症因子的水平呈正相关。（2）肝纤维化微环境促进Dll4和SDF-1依赖的T细胞谱系重建。（3）系统分析低氧条件下MSCs的蛋白表达谱，发现其分泌的胰岛素样生长因子-2（IGF-2）是治疗自身免疫性疾病的重要分子；低剂量IGF2优先结合IGF2R赋予巨噬细胞抗炎记忆。（4）炎症因子刺激MSCs通过分泌血管生长因子（VEGFC）促进血管形成和创伤愈合；而IDO调控TSG6介导的MSCs抑制炎症反应。本项目为指导MSCs在肝硬化治疗中的合理应用提供了重要基础。本项目标注的论文共计31篇，如Cell Metabolism、Nature Reviews Nephrology、Nature Reviews Drug Discovery、Molecular Cancer、Science Advances、Cell Death&Differentiation、PNAS等。专利5项，其中申请3项、授权2项；江苏省地方标准1项。