1 St Vincent's Institute of Medical Research , Fitzroy, Australia .
2 Department of Physiology, University of Melbourne , Melbourne, Australia .
Stem Cells Dev. 2017 Dec 15;26(24):1771-1780. doi: 10.1089/scd.2017.0157. Epub 2017 Nov 27.
Cardiac stem cell (CSC) therapy is a promising approach to treat ischemic heart disease. However, the poor survival of transplanted stem cells in the ischemic myocardium has been a major impediment in achieving an effective cell-based therapy against myocardial infarction. Inhibiting mitochondrial fission has been shown to promote survival of several cell types. However, the role of mitochondrial morphology in survival of human CSC remains unknown. In this study, we investigated whether mitochondrial division inhibitor-1 (Mdivi-1), an inhibitor of mitochondrial fission protein dynamin-related protein-1 (Drp1), can improve survival of a novel population of human W8B2 CSCs in hydrogen peroxide (HO)-induced oxidative stress and simulated ischemia-reperfusion injury models. Mdivi-1 significantly reduced HO-induced cell death in a dose-dependent manner. This cytoprotective effect was accompanied by an increased proportion of cells with tubular mitochondria, but independent of mitochondrial membrane potential recovery and reduction of mitochondrial superoxide production. In simulated ischemia-reperfusion injury model, Mdivi-1 given as a pretreatment or throughout ischemia-reperfusion injury significantly reduced cell death. However, the cytoprotective effect of Mdivi-1 was not observed when given at reperfusion. Moreover, the cytoprotective effect of Mdivi-1 in the simulated ischemia-reperfusion injury model was not accompanied by changes in mitochondrial morphology, mitochondrial membrane potential, or mitochondrial reactive oxygen species production. Mdivi-1 also did not affect mitochondrial bioenergetics of intact W8B2 CSCs. Taken together, these experiments demonstrated that Mdivi-1 treatment of human W8B2 CSCs enhances their survival and can be employed to improve therapeutic efficacy of CSCs for ischemic heart disease.
心脏干细胞 (CSC) 疗法是治疗缺血性心脏病的一种很有前途的方法。然而，移植到缺血心肌中的干细胞存活率低，一直是实现基于细胞的心肌梗死有效治疗的主要障碍。抑制线粒体裂变已被证明可以促进几种细胞类型的存活。然而，线粒体形态在人 CSC 存活中的作用尚不清楚。在这项研究中，我们研究了线粒体分裂抑制剂-1 (Mdivi-1) 是否可以改善新型人 W8B2 CSC 在过氧化氢 (HO) 诱导的氧化应激和模拟缺血再灌注损伤模型中的存活率，Mdivi-1 是一种抑制线粒体裂变蛋白动力相关蛋白 1 (Drp1) 的抑制剂。Mdivi-1 呈剂量依赖性显著降低 HO 诱导的细胞死亡。这种细胞保护作用伴随着管状线粒体比例的增加，但与线粒体膜电位恢复和减少线粒体超氧化物产生无关。在模拟缺血再灌注损伤模型中，Mdivi-1 作为预处理或在整个缺血再灌注损伤期间给予可显著降低细胞死亡。然而，在再灌注时给予 Mdivi-1 时未观察到细胞保护作用。此外，Mdivi-1 在模拟缺血再灌注损伤模型中的细胞保护作用与线粒体形态、线粒体膜电位或线粒体活性氧产生的变化无关。Mdivi-1 也不影响完整 W8B2 CSC 的线粒体生物能。总之，这些实验表明，Mdivi-1 处理人 W8B2 CSC 可增强其存活能力，并可用于提高 CSC 治疗缺血性心脏病的疗效。
