骨髓间充质干细胞对周细胞转化-肾脏纤维化的治疗作用及机制研究

项目名称： 骨髓间充质干细胞对周细胞转化-肾脏纤维化的治疗作用及机制研究

项目编号： No.81470996

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王楠

作者单位： 大连医科大学

项目金额： 73万元

中文摘要： 肌成纤维细胞活化导致的肾小管间质纤维化是慢性肾脏病的共同通路。新近证实周细胞是肌成纤维细胞的主要来源，可能成为肾脏纤维化治疗的新靶点。间充质干细胞能减轻肾小管间质纤维化，但机制未明。我们发现骨髓间充质干细胞可抑制体外原代肾脏周细胞-肌成纤维细胞转化，初步认为对周细胞转化的抑制是干细胞治疗肾脏纤维化的可能机制。研究关注骨髓间充质干细胞是否通过抑制周细胞-肌成纤维细胞转化而减轻肾小管间质纤维化，并探究其作用机制。基于周细胞荧光报告小鼠单侧输尿管结扎肾纤维化模型，观察干细胞对周细胞转化的影响；示踪干细胞在体内的动态分布，明确其作用方式；周细胞转化微环境下，基因表达谱芯片筛选干细胞候选细胞因子,干扰或基因敲除干细胞候选因子表达及建立周细胞特异候选细胞因子受体基因条件性敲除小鼠，体内/外验证其作用及干细胞疗效机制。研究可为肾纤维化治疗提供新思路，并为干细胞在肾脏病中的临床应用提供新的理论依据。

中文关键词： 骨髓间充质干细胞；肾脏；周细胞；肌成纤维细胞；纤维化

英文摘要： Tubulointerstitial fibrosis induced by myofibroblastic activation is the common final outcome of all progressive chronic kidney diseases (CKD). Recent studies have suggested that pericyte is the predominant precursor of myo?broblast in the process of ?brosis. Therefore, new therapeutic strategies targeting pericyte-myofibroblast transition are very promising to ameliorate renal fibrosis. Recent studies have found that mesenchymal stem cells (MSCs) could ameliorate tubulointerstitial fibrosis, however, the underlying mechanism remains unclarified. Our previous study found that MSCs could inhibit the transition of primary cultured pericyte to myofibroblast in vitro. We suggest that the inhibition of pericytic transition may be the principal mechanism for MSCs to exert their therapeutic effect on renal fibrosis.The main concerns of our research are the effects and the underlying mechanisms of bone-marrow derived MSCs on pericyte-myofibroblast transition and tubulointerstitial fibrosis. First, pericyte-florescence reporter mice model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) will be established, then the effects of MSCs on renal fibrosis and pericyte-myofibroblast transition will be evaluated. Second, to investigate the way through which MSCs exert their effects, the dynamic distribution of MSCs after injection will be traced in vivo. Finally, gene expression profile will be analyzed to screen the candidate cytokine(s) of MSCs in the microenvironment of pericytic transition, then the expression(s) of the candidate(s) will be knock-downed by small interfering RNA (siRNA) or by gene knockout, and pericyte-specific conditional gene knockout of candidate(s) receptor mice model will be established, the role of the candidate will be evaluated and the mechanism of MSCs exerting the beneficial effect will be further verified both in vivo and in vitro. We believe that our findings will provide a novel therapeutic strategy for renal fibrosis, and our findings will also provide a new theoretical basis for the clinical application of MSCs in treating kidney diseases.

英文关键词： mesenchymal stem cells;kidney;pericyte;myofibroblast;fibrosis