Table_2_Mesenchymal Stem Cells Shift Mitochondrial Dynamics and Enhance Oxidative Phosphorylation in Recipient Cells.DOCX

Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states.

骨髓间充质干细胞（MSCs）是组织工程和再生医学中应用最为广泛的细胞。MSCs通过多种机制促进宿主组织修复，包括供体细胞的植入、细胞信号因子的释放以及将健康的细胞器转移到宿主体内。在本研究中，我们探讨了MSCs对宿主组织中线粒体形态和功能的具体影响。通过培养遗传性线粒体疾病患者的原代细胞以及低级炎症（高脂肪饮食）的体内动物实验模型，我们发现人源MSCs能够改变线粒体功能。将MSCs与来自线粒体疾病患者的皮肤成纤维细胞共培养，能够从裂变状态挽救异常线粒体形态，使其呈现更为融合的外观，这表明MSCs共培养对宿主细胞线粒体网络形成具有影响。体内实验证实，MSCs治疗后宿主组织中的线粒体丰度和线粒体氧气消耗速率均有所提高。此外，微阵列分析鉴定出在MSCs治疗的动物肝脏中差异表达的226个基因，其中细胞信号传导和肌动蛋白细胞骨架调控是关键的上调过程。综上所述，我们的数据表明，MSCs治疗能够挽救受损的线粒体形态，增强宿主的代谢能力，并诱导宿主基因的广泛转移。这些结果突出了MSCs在调节遗传性和病理性疾病状态中线粒体的潜力。