间充质干细胞逆转皮质类固醇激素抗炎作用的机制研究

项目名称： 间充质干细胞逆转皮质类固醇激素抗炎作用的机制研究

项目编号： No.81501366

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈晓栋

作者单位： 苏州大学

项目金额： 18万元

中文摘要： 间充质干细胞（MSCs）可在炎症部位发挥免疫抑制作用，已用于多种疾病的治疗。临床实验发现MSCs与皮质类固醇激素同时使用，两者疗效大受影响。我们证明MSCs与地塞米松（Dex）同时使用无法控制肝纤维化小鼠体内炎症；Dex可通过抑制iNOS的表达，消除MSCs的免疫抑制能力。然而，MSCs如何逆转Dex的抗炎作用尚不明确。前期实验已发现，MSCs与Dex同时使用无法抑制T细胞增殖，此时，MSCs产生VEGF-C；而VEGF-R3抑制剂的使用，可恢复Dex对于T细胞增殖的抑制能力。本课题将通过阻断VEGF-C/VEGF-R3信号传导，明确MSCs通过VEGF-C在体内逆转Dex抗炎作用；探究Dex作用下，MSCs 通过VEGF-C/VEGF-R3信号通路对于T细胞亚群增殖、抗凋亡信号活化的影响，形成MSCs治疗疾病的优化新策略，为明确VEGF-C免疫调控特性，优化MSCs临床应用提供理论依据。

中文关键词： 间充质干细胞；免疫抑制；皮质类固醇激素；炎症

英文摘要： Mesenchymal stem cells （MSCs）are proved to exert therapeutic effects on various inflammatory disorders through their specific chemotaxis toward sites of inflammation and great immunosuppressive capacity. However, the outcomes of MSC therapy in clinical trials are variable, especially when corticosteroids are co-administrated. Previously, we found that concurrent administration of MSCs and Dexamethasone (Dex), a widely used anti-inflammatory corticosteroid drug, could abrogate their both immunosuppressive effects in treatment of mouse liver fibrosis. Dex could abolish immunosuppression of MSCs through interfering STAT1 phosphorylation-prompted expression of inducible nitric oxide synthase (iNOS). But the mechanism by which MSCs reversed the immunosuppressive effect of Dex has not been uncovered. Our preliminary data showed that co-administration of MSCs with Dex could reverse their immunosuppressive effects on T cell proliferation. In addition, a significant increase of VEGF-c production by MSCs was observed. Remarkably, administration of VEGF-R3 inhibitor could regain the immunosuppressive effects of Dex on T cell proliferation. In this project, we aim to further investigate the effects on immune system mediated by the interaction between MSCs and Dex. To define the critical role of VEGF-C/VEGFR-3 pathway in MSC-mediated elimination of immunosuppressive effect of Dex in vivo, we will neutralize VEGF-C and block VEGF-C/VEGFR-3 signal transduction specifically in mouse model. We will examine the effects of MSC-derived VEGF-C on proliferation and anti-apoptosis function associated PI3K/AKT pathway activation in both CD4+ and CD8+ T cells in the presence of Dex, which will help us to obtain an optimizing strategy for MSC-based therapy. This project will provide lots of experimental evidence for identifying the immunoregulatory property of VEGF-C and optimizing the clinical application of MSCs.

英文关键词： Mesenchymal stem cells;Immunosuppression;Corticosteroids;Inflammation