Stone Laura L Hocum, Chappuis Erin, Marquez Maribel, McFalls Edward O, Kelly Rosemary F, Butterick Tammy
Research Service, Minneapolis VA Health Care System, USA.
Department of Surgery, University of Minnesota, USA.
Cell Med. 2019 Mar 6;11:2155179019834938. doi: 10.1177/2155179019834938. eCollection 2019.
Hibernating myocardium is a subset of ischemic cardiac disease characterized by viable but dysfunctional tissue. Standard treatment for hibernating myocardium is coronary artery bypass graft, which reduces arrhythmias and improves survival but does not fully restore function, presenting a gap in currently available treatments. Large animal studies of hibernating myocardium have identified impaired mitochondrial dynamics as a root cause of persistent cardiac dysfunction despite surgical revascularization. This study presents a novel model of hibernating myocardium cardiomyocytes to study active mitochondrial respiration in hibernating myocardium cells, and to test the paracrine effect of mesenchymal stem cells on impaired mitochondrial function. Exposure of cardiomyocytes to hypoxic conditions of 1% oxygen for 24 hours resulted in a phenotype consistent with hibernating myocardium cardiac tissue, including decreased respiratory capacity under high work states, decreased expression of mitochondrial proteins, and preserved cellular viability. Co-culture of hibernating myocardium cardiomyocytes with mesenchymal stem cells restored mitochondrial respiratory function, potentially via an increase in proliferator-activated receptor gamma coactivator 1-alpha-driven mitochondrial biogenesis. Co-culture treatment of hibernating myocardium cardiomyocytes with mesenchymal stem cells shows improvement in both mitochondrial function and ATP production, both of which are critical for effectively functioning cardiac tissue. These results suggest that mesenchymal stem cell therapy as an adjunct treatment to revascularization may address the current gap in treatment for hibernating myocardium patients.
冬眠心肌是缺血性心脏病的一个子集，其特征是心肌组织存活但功能失调。冬眠心肌的标准治疗方法是冠状动脉搭桥术，该方法可减少心律失常并提高生存率，但不能完全恢复心脏功能，这是目前现有治疗方法中的一个空白。对冬眠心肌的大型动物研究已经确定，尽管进行了手术血运重建，但线粒体动力学受损是导致持续性心脏功能障碍的根本原因。本研究提出了一种新的冬眠心肌细胞模型，用于研究冬眠心肌细胞中的活跃线粒体呼吸，并测试间充质干细胞对受损线粒体功能的旁分泌作用。将心肌细胞暴露于1%氧气的低氧条件下24小时，会导致出现与冬眠心肌组织一致的表型，包括高工作状态下呼吸能力下降、线粒体蛋白表达降低以及细胞活力得以保留。将冬眠心肌细胞与间充质干细胞共培养可恢复线粒体呼吸功能，这可能是通过增加过氧化物酶体增殖物激活受体γ共激活因子1α驱动的线粒体生物合成来实现的。用间充质干细胞对冬眠心肌细胞进行共培养处理后，线粒体功能和ATP生成均得到改善，这两者对于心脏组织的有效功能发挥都至关重要。这些结果表明，间充质干细胞疗法作为血运重建的辅助治疗方法，可能会填补目前冬眠心肌患者治疗方面的空白。
