Liang Xiaoting, Zhang Yuelin, Lin Fang, Li Mimi, Li Xin, Chen Yu, Liu Jing, Meng Qingshu, Ma Xiaoxue, Wang Enhao, Wei Lu, He Zhiying, Fan Huimin, Zhou Xiaohui, Ding Yue, Liu Zhongmin
Institute for Regenerative Medicine Shanghai East Hospital, School of Life Sciences and Technology, Tongji University Shanghai People's Republic of China.
Clinical Translational Medical Research Center Shanghai East Hospital, Tongji University School of Medicine Shanghai People's Republic of China.
Bioeng Transl Med. 2022 Jul 2;8(1):e10365. doi: 10.1002/btm2.10365. eCollection 2023 Jan.
Mitochondrial dysfunction is considered to be a key contributor to the development of heart failure. Replacing injured mitochondria with healthy mitochondria to restore mitochondrial bioenergy in myocardium holds great promise for cardioprotection after infarction. This study aimed to investigate whether direct transplantation of exogenous mitochondria derived from mesenchymal stem cells (MSC-mt) is beneficial and superior in protecting cardiac function in a mouse model of myocardial infarction (MI) compared to mitochondria derived from skin fibroblast (FB-mt) and to explore the underlying mechanisms from their effects on the endothelial cells. The isolated MSC-mt presented intact mitochondrial morphology and activity, as determined by electron microscopy, JC-1 mitochondrial membrane potential assay, and seahorse assay. Direct injection of MSC-mt into the peri-infarct region in a mouse MI model enhanced blood vessel density, inhibited cardiac remodeling and apoptosis, thus improving heart function compared with FB-mt group. The injected MSC-mt can be tracked in the endothelial cells. In vitro, the fluorescence signal of MSC-mt can be detected in human umbilical vein endothelial cells (HUVECs) by confocal microscopy and flow cytometry after coculture. Compared to FB-mt, MSC-mt more effectively protected the HUVECs from oxidative stress-induced apoptosis and reduced mitochondrial production of reactive oxygen species. MSC-mt presented superior capacity in inducing tube formation, enhancing SCF secretion, ATP content and cell proliferation in HUVECs compared to FB-mt. Mechanistically, MSC-mt administration alleviated oxidative stress-induced endothelial senescence via activation of ERK pathway. These findings suggest that using MSCs as sources of mitochondria is feasible and that proangiogenesis could be the mechanism by which MSC-mt transplantation attenuates MI. MSC-mt transplantation might serve as a new therapeutic strategy for treating MI.
线粒体功能障碍被认为是心力衰竭发展的关键因素。用健康的线粒体替代受损的线粒体以恢复心肌中的线粒体生物能量，对心肌梗死后的心脏保护具有巨大潜力。本研究旨在探讨与皮肤成纤维细胞来源的线粒体（FB-mt）相比，直接移植间充质干细胞来源的外源性线粒体（MSC-mt）在心肌梗死（MI）小鼠模型中保护心脏功能方面是否有益且更具优势，并从其对内皮细胞的影响中探索潜在机制。通过电子显微镜、JC-1线粒体膜电位测定和海马分析确定，分离出的MSC-mt呈现完整的线粒体形态和活性。与FB-mt组相比，在小鼠MI模型中将MSC-mt直接注射到梗死周边区域可提高血管密度，抑制心脏重塑和细胞凋亡，从而改善心脏功能。注入的MSC-mt可在内皮细胞中被追踪到。在体外，共培养后通过共聚焦显微镜和流式细胞术可在人脐静脉内皮细胞（HUVECs）中检测到MSC-mt的荧光信号。与FB-mt相比，MSC-mt能更有效地保护HUVECs免受氧化应激诱导的凋亡，并减少线粒体活性氧的产生。与FB-mt相比，MSC-mt在诱导HUVECs形成管腔、增强干细胞因子（SCF）分泌、ATP含量和细胞增殖方面具有更强的能力。机制上，给予MSC-mt可通过激活ERK途径减轻氧化应激诱导的内皮细胞衰老。这些发现表明，将间充质干细胞作为线粒体来源是可行的，促血管生成可能是MSC-mt移植减轻心肌梗死的机制。MSC-mt移植可能成为治疗心肌梗死的一种新的治疗策略。
