巨噬细胞膜封装CD51+bMSCs外泌体趋向心梗组织调节SOX17重建冠脉微循环的研究

我们前期发现，骨髓CD51阳性干细胞（CD51+bMSCs）治疗可促进心梗小鼠心脏康复，但移植的细胞在心肌内无法长期存活，且有成球增殖的问题。深入研究发现，CD51+bMSCs分泌的外泌体（CD51+bMSCs-Exo）可解决上述问题，其经心肌内注射对AMI有疗效，但静脉注射效果差，这与外泌体趋附至心梗区数量少有关。基于巨噬细胞具有定向趋化至炎性区的特点，我们提出巨噬细胞膜封装CD51+bMSCs-Exo（简称：ME复合体）可以解决外泌体自身趋化能力差的问题。预实验结果提示：1）ME复合体静脉应用后可趋向富集至损伤心肌并促进心梗康复；2）心梗区出现大量的新生血管可以重建冠脉微循环；3）ME复合体激活了内皮细胞SOX17/VEGFR促进血管新生。本项目将采用内皮细胞SOX17基因敲除小鼠和原代内皮细胞深入研究，阐明ME复合体促进心梗康复的具体机制，为外泌体在心梗疾病的转化临床应用提供新思路。

Previously, we found that transplantation of bone marrow derived CD51 positive cells (CD51+bMSCs) promoted cardiac recovery in mice with myocardial infarction. However, there are problems such as short survival time of transplanted cells in the injured myocardium and ball-like proliferation potential. Further, we have discovered that the transplantation of exosomes secreted by CD51+bMSCs (CD51+bMSCs-Exo) to mice with AMI avoided the above problems, and effectively improved heart function via intramyocardial injection but not intravenous injection. The unequal effects were contributed to the different number of exosomes that attached to the injured tissues. Based on the chemotactic characteristics of macrophages to inflammatory tissues, we supposed that the chemotactic capacity of CD51+bMSCs-Exo could be improved when they encapsulated with macrophage membrane (abbreviation: ME complex).In our preliminary experiment, data showed that: 1) ME complex migrated to the injured myocardium after intravenous delivery and promoted the recovery of infarcted myocardium.2) A large number of new blood vessels were emerged in the injured myocardium, which reconstructed coronary microcirculation. 3) ME complex activates SOX17/VEGFR of endothelial cells to promote angiogenesis. Further, we will use SOX17 Tie2 Ki transgene mice and SOX17 silenced primary endothelial to explore the mechanism of ME complex on rehabilitation of myocardial infarction, which could provide new sights for the translational clinical application of exosomes to myocardial infarction patients.