aGVHD引发的细胞因子风暴通过损害受者MSC的自我更新能力阻碍移植后骨髓微环境重建

项目名称： aGVHD引发的细胞因子风暴通过损害受者MSC的自我更新能力阻碍移植后骨髓微环境重建

项目编号： No.81500083

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： 丁丽

作者单位： 中国人民解放军第四军医大学

项目金额： 18万元

中文摘要： 间充质干细胞（MSC）是骨髓微环境重要成分，它既分化为多种细胞，参与造血干细胞移植后骨髓微环境重建，又能自我更新，为修复骨髓微环境提供充足种子。有研究表明，急性移植物抗宿主（aGVHD)引发的细胞因子风暴损伤骨髓微环境，影响移植后造血重建，但具体机制不明。我们最近研究发现aGVHD患者骨髓MSC自我更新能力下降，且与风暴因子TNF-α，IL-1β和IL-17A密切相关。结合二代测序技术和生物信息学分析，我们发现相关风暴因子抑制MSC表达自我更新相关蛋白Sca-1。而目前国内外研究未见aGVHD通过影响MSC自我更新能力干扰移植后骨髓微环境重建的报道。本课题拟采集临床标本并建立aGVHD小鼠模型，在体内外研究aGVHD对受者MSC自我更新的影响及其机制。本课题有望为骨髓微环境研究提供理论积累，为优化aGVHD治疗提供实践依据。

中文关键词： 急性移植物抗宿主病；骨髓微环境；间充质干细胞；自我更新；细胞因子风暴

英文摘要： Mesenchymal stem cell (MSC) has been an important cellular component of the bone marrow microenvironment due to its multi-differentiation capacity. In addition, MSC supplies abundant seed cells for the bone marrow niche rebulding by consistent self-replication, namely “self-renewal”. It had been demonstrated that aGVHD induced the cytokine storm and damaged the bone marrow microenvironment but the precise mechanisms remain unknown. Our recent works showed that the self-renewal capacity of aGVHD receipients derived MSC was impaired and the effect was closely bound up with the proinflammatory cytokines such as TNF-α，IL-1β and IL-17A. Based on the sequencing technology and bioinformatics analysis, we discovered that the cytokines suppressed the expression of stem cell antigen 1 which modulated the self-renewal of MSC. However, the study about aGVHD hinder the rebuilding of bone marrow niche via impairing the self-renewal of MSC have not been reported. Hence, this proposed study will mechanistically investigate the influence of aGVHD on the self-renewal of receipient MSC by using clinical samples and mouse models in vivo and in vitro. This study will shed light on the comprehensive understanding of the bone marrow microenvironment; thus contribute to the improvement of aGVHD therapy.

英文关键词： aGVHD;bone marrow microenvironment;MSC;self-renewal;cytokine storm