凋亡MSCs刺激单核-巨噬细胞分泌外泌体对急性心肌梗死心肌修复的新机制

项目名称： 凋亡MSCs刺激单核-巨噬细胞分泌外泌体对急性心肌梗死心肌修复的新机制

项目编号： No.81470470

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： 沈成兴

作者单位： 上海交通大学

项目金额： 73万元

中文摘要： 急性心肌梗死（AMI）后心肌细胞再生治疗中炎症细胞起着关键作用。我们的前期研究表明，MSCs移植治疗AMI主要是浸润至梗死区的巨噬细胞吞噬凋亡MSCs，分泌Ang-1、VEGF和IGF-1等细胞因子，促进了损伤心肌的修复；进一步研究发现，活化的巨噬细胞能分泌较多外泌体，改善干细胞移植微环境；但外泌体成分复杂，其发挥保护作用的组分及机制未明。我们提出假说：巨噬细胞吞噬凋亡的MSC后分泌的外泌体在AMI后心肌修复中起关键作用。据此，本项目以吞噬了凋亡MSCs的巨噬细胞及外泌体为研究对象，拟：①阐述巨噬细胞外泌体对心肌细胞活力以及心肌干细胞分化的影响，筛选有益心肌存活和修复的外泌体成分；②探讨经NF-kappa B/Heparanase/Sydecan-1路径调节巨噬细胞外泌体的机制；③体内验证好外泌体抑制心肌损伤、促进干细胞再生的作用机制。本研究将揭示AMI后干细胞移植治疗的新机制。

中文关键词： 急性心肌梗死；骨髓间充质干细胞；单核-巨噬细胞；外泌体

英文摘要： The inflammatory cells play a key role in cardiomyocyte regeneration therapy after acute myocardial infarction. Our preliminary study had found the main mechanism of the MSCs transplantation was that monocytes/macrophages infiltrating into the infarction zone phagocytized dead MSCs and subsequently secreted a variety of cytokines such as Ang-1, VEGF-α, IGF-1 which contributed to the repairation of the myocardium. Then we further found that the activated macrophages were able to secret a number of exosomes which can lead to better microenvironment in the infarction zone.However,in view of the complexity of the composition for exosomes, we still know little about the exact contents and mechanisms in the repairation of the myocardium.Thus,we give the hypothesis that the cirtical mechanism of MSCs repairation after AMI is the exosomes excreted by the macrophages which phagocytied apoptic MSCs. So,we will ① to explore the mechanisms of macrophage exosomes stimulated by apoptotic MSCs,screen the ingredients of the exosomes which are benefit to the viability of cardiac cells as well as the differentiation of cardiac stem cells ex vivo.②to explore the regulative mechanisms of exosomes secreted by macrophages through NF-kappa B/Heparanase/Sydecan-1 pathway. ③ to verify the efficacy of the exosomes derived from macrophages phagocytized apopotic MSCs in vivo in AMI mouse model. This study will give the new idea that the exosomes secreted by the macrophages which had phagocytized the dead MSCs are the main mechanism in myocardial MSCs repairation.

英文关键词： acute myocardial infarction;mesenchymal stem cells;mono-macrophage;exosome