骨髓间充质干细胞旁分泌CTRP3水平影响心肌梗死疗效及机制

项目名称： 骨髓间充质干细胞旁分泌CTRP3水平影响心肌梗死疗效及机制

项目编号： No.81470477

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： 孙阳

作者单位： 中国人民解放军第四军医大学

项目金额： 73万元

中文摘要： 骨髓间充质干细胞（MSCs）移植是心肌梗死（MI）治疗研究热点，但临床试验效果仍不理想。临床试验采用自体MSCs移植多源于衰老个体，是否影响MSCs治疗MI疗效及其机制尚未明确。我们前期研究发现外源性C1q肿瘤坏死因子相关蛋白3（CTRP3）在MI中激活Akt通路抑制心肌间质纤维化及心肌细胞凋亡，发挥缺血心肌保护作用(Circulation)，且预实验结果发现衰老大鼠MSCs分泌CTRP3显著降低，由此提出假说：MSCs旁分泌CTRP3可激活心肌Akt通路抑制心肌间质纤维化及心肌细胞凋亡，对MI发挥重要调控作用，衰老MSCs低分泌CTRP3可影响其疗效。本研究以CTRP3为靶点，运用基因敲除动物、siRNA干预及腺病毒过表达等方法，结合细胞培养和动物MI模型，研究CTRP3年龄相关性分泌对MI影响，揭示衰老MSCs移植影响MI疗效的机制，对提高MSCs治疗MI临床疗效有重要理论指导意义。

中文关键词： 心肌梗死；骨髓间充质干细胞；心肌保护；心肌纤维化

英文摘要： Bone mesenchymal stem cells (MSCs) transplantation gains attention for treating myocardial infarction (MI) with unsatisfactory clinical trial outcomes. Whether MSCs from the aged people affect the therapeutic effect and the underlying mechanism remain unknown. We discovered that C1q/tumor necrosis factor-related protein-3 (CTRP3) treatment protected against ischemic cardiac injury via Akt activation, inhibiting interstitial fibrosis and cardiomyocyte apoptosis (Circulation). Moreover, we discovered in our preliminary experiment that MSCs paracrined CTRP3 which was down-regulated in aged rats. Thus we propose hypothesis that MSCs paracrine CTRP3 which will protect against MI injury by activating Akt pathway and inhibiting interstitial fibrosis and cardiomyocyte apoptosis. The down-regulated CTRP3 level in the aged rats decreases its effect. Using CTRP3 KO rats and adenovirus overexpression method, we will detect how CTRP3 from MSCs regulates MI both in vivo and in vitro, and demonstrate the underlying mechanism, which will improve MSCs therapeutic effect on MI.

英文关键词： myocardial infarction;mesenchymal stem cells;cardiac protection;myocardial fibrosis