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.

中文翻译：

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直接施用间充质干细胞衍生的线粒体通过改善内皮衰老改善梗塞后的心脏功能

线粒体功能障碍被认为是心力衰竭发展的关键因素。用健康的线粒体替换受损的线粒体以恢复心肌中的线粒体生物能对于梗死后的心脏保护具有很大的前景。本研究旨在研究直接移植源自间充质干细胞的外源性线粒体 (MSC-mt) 与源自皮肤成纤维细胞的线粒体 (FB-mt) 相比，在保护心肌梗死 (MI) 小鼠模型的心脏功能方面是否有益和更优) 并探索其对内皮细胞影响的潜在机制。分离的 MSC-mt 呈现完整的线粒体形态和活性，如通过电子显微镜、JC-1 线粒体膜电位测定和海马测定所确定的。与FB-mt组相比，在小鼠MI模型的梗死周围区域直接注射MSC-mt可增强血管密度，抑制心脏重塑和细胞凋亡，从而改善心功能。可以在内皮细胞中追踪注射的 MSC-mt。在体外，共培养后，可以通过共聚焦显微镜和流式细胞仪检测人脐静脉内皮细胞 (HUVEC) 中的 MSC-mt 荧光信号。与 FB-mt 相比，MSC-mt 更有效地保护 HUVEC 免受氧化应激诱导的细胞凋亡并减少线粒体活性氧的产生。与 FB-mt 相比，MSC-mt 在诱导管形成、增强 HUVEC 中的 SCF 分泌、ATP 含量和细胞增殖方面表现出卓越的能力。从机械上讲，MSC-mt 给药通过激活 ERK 通路减轻氧化应激诱导的内皮衰老。这些发现表明使用 MSCs 作为线粒体来源是可行的，并且促血管生成可能是 MSC-mt 移植减轻 MI 的机制。MSC-mt 移植可能作为治疗 MI 的新治疗策略。