Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
IonsGate Preclinical Services Inc, Vancouver, BC V6T 1Z3, Canada.
Int J Mol Sci. 2020 Jan 19;21(2):657. doi: 10.3390/ijms21020657.
There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion channel or ion channel-modulatory proteins. Thus far, the electrophysiological phenotype of these mutations has been typically studied using transgenic animal models and heterologous expression systems. Although they have played a major role in advancing the understanding of the pathophysiology of arrhythmogenesis, more physiological and predictive preclinical models are necessary to optimize the treatment strategy for individual patients. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have generated much interest as an alternative tool to model arrhythmogenic diseases. They provide a unique opportunity to recapitulate the native-like environment required for mutated proteins to reproduce the human cellular disease phenotype. However, it is also important to recognize the limitations of this technology, specifically their fetal electrophysiological phenotype, which differentiates them from adult human myocytes. In this review, we provide an overview of the major inherited arrhythmogenic cardiac diseases modeled using hiPSC-CMs and for which the cellular disease phenotype has been somewhat characterized.
需要改进遗传性心脏病的体外模型，以更好地理解基本的细胞和分子机制，并推进药物开发。这些疾病大多数都与心律失常有关，其原因是离子通道或离子通道调节蛋白的突变。到目前为止，这些突变的电生理表型通常使用转基因动物模型和异源表达系统进行研究。尽管它们在推进心律失常发生的病理生理学理解方面发挥了重要作用，但需要更生理和预测性的临床前模型来优化针对个体患者的治疗策略。人类诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）作为心律失常疾病模型的替代工具引起了广泛关注。它们为复现突变蛋白所需的类似天然的环境提供了独特的机会，从而再现人类细胞疾病表型。然而，也有必要认识到这项技术的局限性，特别是它们的胎儿电生理表型，这使它们与成人人类心肌细胞有所不同。在这篇综述中，我们概述了使用 hiPSC-CMs 进行建模的主要遗传性心律失常性心脏病，并对其细胞疾病表型进行了一定程度的描述。
