Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
J Cell Physiol. 2019 Aug;234(8):13878-13893. doi: 10.1002/jcp.28070. Epub 2019 Feb 5.
Exosomes extracted from mesenchymal stem cells (MSCs) was reported to reduce myocardial ischemia/reperfusion damage. Besides, stromal-derived factor 1 (SDF1a) functions as cardiac repair after myocardial infarction (MI). Therefore, the present study aims to identify whether exosomes (Exo) released from SDF1-overexpressing MSCs display a beneficial effect on ischemic myocardial infarction. Initially, a gain-of-function study was performed to investigate the function of SDF1 in ischemic myocardial cells and cardiac endothelial cells. Coculture experiments were performed to measure potential exosomic transfer of SDF1 from MSCs to ischemic myocardial cells and cardiac endothelial cells. During the coculture experiments, exosome secretion was disrupted by neutral sphingomyelinase inhibitor GW4869 and upregulated exosomal SDF1 using SDF1 plasmid. Effects of Exo-SDF1 on cardiac function in MI mice were investigated in vivo. MSCs suppressed myocardial cell apoptosis and promoted microvascular regeneration of endothelial cells through secretion of exosomes. The addition of GW4869 led to increased apoptotic capacity of myocardial cells, decreased microvascular formation ability of endothelial cells, enhanced autophagy ability, and elevated Beclin-1 level as well as ratio of LC3II/LC3I. Overexpression of SDF1 and Exo-SDF1 inhibited apoptosis and autophagy of myocardial cells, but promoted tube formation of endothelial cells. The interference of PI3K signaling pathway promoted apoptosis and autophagy of myocardial cells, but inhibited tube formation of endothelial cells. SDF1 activated the PI3K signaling pathway. Exo-SDF1 protected cardiac function of MI mice and inhibited myocardial tissue damage. This study provided evidence that SDF1 overexpression in MSCs-derived exosomes inhibited autophagy of ischemic myocardial cells and promoted microvascular production of endothelial cells.
从间充质干细胞（MSCs）中提取的外泌体被报道可减轻心肌缺血/再灌注损伤。此外，基质衍生因子 1（SDF1a）在心肌梗死后发挥心脏修复作用。因此，本研究旨在确定 SDF1 过表达的 MSC 释放的外泌体是否对缺血性心肌梗死具有有益作用。首先，进行了一项功能获得研究，以研究 SDF1 在缺血性心肌细胞和心脏内皮细胞中的功能。进行共培养实验以测量 SDF1 从 MSC 到缺血性心肌细胞和心脏内皮细胞的潜在外泌体转移。在共培养实验中，通过中性鞘磷脂酶抑制剂 GW4869 破坏外泌体分泌，并使用 SDF1 质粒上调外泌体 SDF1。体内研究了 Exo-SDF1 对 MI 小鼠心功能的影响。MSCs 通过分泌外泌体抑制心肌细胞凋亡并促进内皮细胞微血管再生。添加 GW4869 导致心肌细胞凋亡能力增加、内皮细胞微血管形成能力降低、自噬能力增强以及 Beclin-1 水平和 LC3II/LC3I 比值升高。SDF1 的过表达和 Exo-SDF1 抑制了心肌细胞的凋亡和自噬，但促进了内皮细胞的管形成。PI3K 信号通路的干扰促进了心肌细胞的凋亡和自噬，但抑制了内皮细胞的管形成。SDF1 激活了 PI3K 信号通路。Exo-SDF1 保护 MI 小鼠的心功能并抑制心肌组织损伤。本研究提供的证据表明，MSC 来源的外泌体中 SDF1 的过表达抑制了缺血性心肌细胞的自噬并促进了内皮细胞的微血管生成。
