Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China.
Stem Cells Dev. 2021 Apr 1;30(7):386-398. doi: 10.1089/scd.2020.0149. Epub 2021 Mar 22.
Declined function of aged mesenchymal stem cells (MSCs) diminishes the benefits of cell therapy for myocardial infarction (MI). Our previous study has demonstrated that SRT1720, a specific SIRT1 activator, could protect aged human MSCs (hMSCs) against apoptosis. The purpose of the present study was to investigate the role of mitochondria in the antiapoptotic effects of SRT1720. In addition, we established a nonhuman primate MI model to evaluate cell engraftment of SRT1720-pretreated aged hMSCs (SRT1720-OMSCs). A hydrogen peroxide (HO)-induced apoptosis model was established in vitro to mimic MI microenvironment. Compared with vehicle-treated aged hMSCs (Vehicle-OMSCs), SRT1720-OMSCs showed alleviated apoptosis level, significantly decreased caspase-3 and caspase-9 activation, and reduced release of cytochrome when subjected to HO treatment. Mitochondrial contents were compared between young and aged hMSCs and our data showed that aged hMSCs had lower mitochondrial DNA (mtDNA) copy numbers and protein expression levels of components of the mitochondrial electron transport chain (ETC) than young hMSCs. Also, treatment with SRT1720 resulted in enhanced MitoTracker staining, increased mtDNA levels and expression of mitochondrial ETC components in aged hMSCs. Furthermore, SRT1720-OMSCs exhibited elevated mitochondrial respiratory capacity and higher mitochondrial membrane potential. In vivo study demonstrated that SRT1720-OMSCs had higher engraftment rates than Vehicle-OMSCs at 3 days after transplantation into the infarcted nonhuman primate hearts. Taken together, these results suggest that SRT1720 promotes mitochondrial biogenesis and function of aged hMSCs, which is involved in its protective effects against HO-induced apoptosis. These findings encourage further exploration of the optimization of aged stem cells function via regulating mitochondrial function.
衰老间充质干细胞（MSCs）功能下降会降低细胞疗法治疗心肌梗死（MI）的效果。我们之前的研究表明，SRT1720 是一种特异性 SIRT1 激活剂，可保护衰老的人 MSCs（hMSCs）免受凋亡。本研究旨在探讨线粒体在 SRT1720 抗凋亡作用中的作用。此外，我们建立了非人灵长类动物 MI 模型，以评估 SRT1720 预处理衰老 hMSCs（SRT1720-OMSCs）的细胞移植情况。体外建立了过氧化氢（HO）诱导的凋亡模型，以模拟 MI 微环境。与用载体处理的衰老 hMSCs（Vehicle-OMSCs）相比，SRT1720-OMSCs 在受到 HO 处理时，凋亡水平降低，caspase-3 和 caspase-9 活性显著降低，细胞色素 c 释放减少。比较了年轻和衰老 hMSCs 之间的线粒体含量，我们的数据表明衰老 hMSCs 的线粒体 DNA（mtDNA）拷贝数和线粒体电子传递链（ETC）组成部分的蛋白表达水平低于年轻 hMSCs。此外，用 SRT1720 处理后，衰老 hMSCs 的 MitoTracker 染色增强，mtDNA 水平和线粒体 ETC 组成部分的表达增加。此外，SRT1720-OMSCs 的线粒体呼吸能力提高，线粒体膜电位更高。体内研究表明，在移植到非人灵长类动物梗死心脏 3 天后，SRT1720-OMSCs 的植入率高于 Vehicle-OMSCs。总之，这些结果表明 SRT1720 促进衰老 hMSCs 的线粒体生物发生和功能，这与其对 HO 诱导的凋亡的保护作用有关。这些发现鼓励进一步探索通过调节线粒体功能优化衰老干细胞功能。
