Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes.
Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes.
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使用患者诱导多能干细胞衍生的心肌细胞研究SCO2介导的肥厚性心肌病的心脏病理。
DOI：
10.1111/jcmm.13392
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发表时间：
2018-03
影响因子：
5.3
通讯作者：
Binah O
中科院分区：
文献类型：
--
作者：
Hallas T;Eisen B;Shemer Y;Ben Jehuda R;Mekies LN;Naor S;Schick R;Eliyahu S;Reiter I;Vlodavsky E;Katz YS;Õunap K;Lorber A;Rodenburg R;Mandel H;Gherghiceanu M;Binah O
SCO2 突变是 COX 缺乏的最常见原因之一，导致线粒体氧化 ATP 生成能力降低，通常导致肥厚型心肌病 (HCM)。迄今为止，最近的相关报告都没有提供对 SCO2 疾病病理生理学的深入了解。为了研究该疾病的心脏病理学，我们第一个从 SCO2 突变患者中产生诱导多能干细胞 (iPSC) 衍生的心肌细胞 (iPSC-CM)。为了生成 iPSC，我们对两名 SCO2 患者和健康对照的皮肤成纤维细胞进行了重新编程。第一个患者是常见 E140K 突变的复合杂合子，第二个患者是不太常见的 G193S 突变的纯合子。 iPSC 通过类胚体 (EB) 形成分化为心肌细胞。为了检验 SCO2 突变与线粒体异常以及细胞内 Ca2+ 超载导致功能紊乱和心律失常相关的假设，我们研究了 SCO2 突变的 iPSC-CM（与对照心肌细胞相比）：（i）超微结构变化； (ii) 对β-肾上腺素能刺激、[Ca2+]o 和血管紧张素-II (AT-II) 增加的正性肌力反应； (iii) 节拍率变异性 (BRV) 特性。为了支持这一假设，我们在突变的 iPSC-CM 中发现了主要的超微结构异常，对正性肌力干预和咖啡因的反应显着减弱，以及后除极延迟 (DAD) 和 BRV 增加，表明由于 ATP 短缺导致 SERCA 活性减弱，SR Ca2+ 处理能力受损。我们的新结果表明 iPSC-CM 可用于研究 SCO2 突变综合征的病理生理机制。
Mutations in SCO2 are among the most common causes of COX deficiency, resulting in reduced mitochondrial oxidative ATP production capacity, often leading to hypertrophic cardiomyopathy (HCM). To date, none of the recent pertaining reports provide deep understanding of the SCO2 disease pathophysiology. To investigate the cardiac pathology of the disease, we were the first to generate induced pluripotent stem cell (iPSC)‐derived cardiomyocytes (iPSC‐CMs) from SCO2‐mutated patients. For iPSC generation, we reprogrammed skin fibroblasts from two SCO2 patients and healthy controls. The first patient was a compound heterozygote to the common E140K mutation, and the second was homozygote for the less common G193S mutation. iPSC were differentiated into cardiomyocytes through embryoid body (EB) formation. To test the hypothesis that the SCO2 mutation is associated with mitochondrial abnormalities, and intracellular Ca2+‐overload resulting in functional derangements and arrhythmias, we investigated in SCO2‐mutated iPSC‐CMs (compared to control cardiomyocytes): (i) the ultrastructural changes; (ii) the inotropic responsiveness to β‐adrenergic stimulation, increased [Ca2+]o and angiotensin‐II (AT‐II); and (iii) the Beat Rate Variability (BRV) characteristics. In support of the hypothesis, we found in the mutated iPSC‐CMs major ultrastructural abnormalities and markedly attenuated response to the inotropic interventions and caffeine, as well as delayed afterdepolarizations (DADs) and increased BRV, suggesting impaired SR Ca2+ handling due to attenuated SERCA activity caused by ATP shortage. Our novel results show that iPSC‐CMs are useful for investigating the pathophysiological mechanisms underlying the SCO2 mutation syndrome.
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影响因子：
5.3
作者：
Novak A;Barad L;Lorber A;Gherghiceanu M;Reiter I;Eisen B;Eldor L;Itskovitz-Eldor J;Eldar M;Arad M;Binah O
通讯作者：
Binah O
影响因子：
3.5
作者：
Jaksch, M;Ogilvie, I;Shoubridge, EA
通讯作者：
Shoubridge, EA
影响因子：
15.9
作者：
Spindler, M;Saupe, KW;Ingwall, JS
通讯作者：
Ingwall, JS
影响因子：
5.2
作者：
Dolnikov, Katya;Shilkrut, Mark;Binah, Ofer
通讯作者：
Binah, Ofer
DOI：
10.1152/ajpheart.00705.2013
发表时间：
2014-05-01
影响因子：
4.8
作者：
Stoehr, Andrea;Neuber, Christiane;Hansen, Arne
通讯作者：
Hansen, Arne