Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.
Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.
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DOI：
10.1161/jaha.114.001263
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发表时间：
2014-11-11
影响因子：
5.4
通讯作者：
Fukuda K
中科院分区：
文献类型：
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作者：
Tanaka A;Yuasa S;Mearini G;Egashira T;Seki T;Kodaira M;Kusumoto D;Kuroda Y;Okata S;Suzuki T;Inohara T;Arimura T;Makino S;Kimura K;Kimura A;Furukawa T;Carrier L;Node K;Fukuda K
尽管对肥厚型心肌病（HCM）的遗传和分子研究越来越多，但就遗传-环境相互作用而言，这种疾病如何在病理和临床上发生和发展仍不清楚。建立HCM的人类疾病模型将有助于阐明这些疾病机制;然而，来自患者的心肌细胞不易用于基础研究。患者特异性诱导多能干细胞（iPSC）可能为破译HCM的发病机制带来很大希望。本研究的目的是阐明HCM疾病进展中遗传背景和环境因素之间的相互作用。我们从3名HCM患者和3名健康对照受试者中产生iPSC，并分化心肌细胞。基于形态学特性和高速视频成像表征HCM病理表型。对照和HCM iPSC衍生的心肌细胞之间的差异在基线条件下在病理学特征方面是轻微的。为了鉴定候选的疾病促进环境因子，通过几种心肌细胞肥大促进因子刺激心肌细胞。有趣的是，内皮素-1强烈诱导HCM iPSC衍生的心肌细胞中的病理表型，如心肌细胞肥大和细胞内肌原纤维紊乱。然后，我们在来自杂合Mybpc 3靶向敲除小鼠的新生心肌细胞中复制了这些表型。具有运动矢量预测的高速视频成像描绘了iPSC衍生的心肌细胞中的生理收缩动力学，其揭示了由内皮素-1刺激的自搏动HCM iPSC衍生的单个心肌细胞显示出可变的收缩方向。患者的遗传背景和环境因素内皮素-1之间的相互作用促进了HCM iPSC衍生心肌细胞中的HCM病理表型和收缩变异性。
Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic–environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient‐specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high‐speed video imaging. The differences between control and HCM iPSC‐derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease‐promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy‐promoting factors. Interestingly, endothelin‐1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC‐derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3‐targeted knock in mice. High‐speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC‐derived cardiomyocytes, which revealed that self‐beating HCM iPSC‐derived single cardiomyocytes stimulated by endothelin‐1 showed variable contractile directions. Interactions between the patient's genetic backgrounds and the environmental factor endothelin‐1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC‐derived cardiomyocytes.