Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells.
Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells.
复制标题
线粒体通透性转换孔和氧化还原信号的双重调节协同促进心肌细胞从多能干细胞分化。
DOI：
10.1161/jaha.113.000693
复制
发表时间：
2014-03-13
影响因子：
5.4
通讯作者：
Koh GY
中科院分区：
文献类型：
--
作者：
Cho SW;Park JS;Heo HJ;Park SW;Song S;Kim I;Han YM;Yamashita JK;Youm JB;Han J;Koh GY
从多能干细胞（PSC）分化的心肌细胞为心脏再生提供了重要的细胞资源。然而，对心肌细胞分化的线粒体代谢和氧化还原调节机制仍知之甚少。在这里，我们表明，抑制线粒体通透性转换孔（mPTP）环孢菌素A（CsA）促进心肌细胞分化的PSC。我们从小鼠和人PSC诱导心肌细胞分化，并检查CsA对分化过程的影响。CsA的心肌形成作用主要是通过抑制mPTP而不是通过抑制钙调神经磷酸酶。mPTP抑制剂NIM811对钙调神经磷酸酶没有抑制作用，但与CsA一样促进心肌细胞分化，但钙调神经磷酸酶抑制剂FK 506仅略微增加心肌细胞分化。CsA处理的细胞显示线粒体钙、线粒体膜电位、耗氧率、ATP水平和与线粒体功能相关的基因表达增加。此外，线粒体氧化代谢的抑制降低CsA的心肌效应，而抗氧化剂处理增强CsA的心肌效应。我们的数据表明，CsA抑制mPTP改变线粒体氧化代谢和氧化还原信号，这导致从PSC分化为功能性心肌细胞。
Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we show that inhibition of the mitochondrial permeability transition pore (mPTP) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSCs. We induced cardiomyocyte differentiation from mouse and human PSCs and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from mPTP inhibition rather than from calcineurin inhibition. The mPTP inhibitor NIM811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK506 only slightly increased cardiomyocyte differentiation. CsA‐treated cells showed an increase in mitochondrial calcium, mitochondrial membrane potential, oxygen consumption rate, ATP level, and expression of genes related to mitochondrial function. Furthermore, inhibition of mitochondrial oxidative metabolism reduced the cardiomyogenic effect of CsA while antioxidant treatment augmented the cardiomyogenic effect of CsA. Our data show that mPTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSCs.