Modelling the long QT syndrome with induced pluripotent stem cells
Modelling the long QT syndrome with induced pluripotent stem cells
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DOI：
10.1038/nature09747
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发表时间：
2011-03-10
期刊：
影响因子：
64.8
通讯作者：
Gepstein, Lior
中科院分区：
文献类型：
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作者：
Itzhaki, Ilanit;Maizels, Leonid;Gepstein, Lior
产生患者特异性人诱导多能干细胞（iPSC）（1-3）的能力为人类疾病建模和个性化药物测试提供了新的范例（4）。先天性长QT综合征（LQTS）是一种家族性致心律失常综合征，其特征为离子通道功能异常和心源性猝死（5-7）。在这里，我们报告了从2型LQTS患者（这是由于KCNH 2基因中的A614 V错义突变）中开发出患者/疾病特异性人iPSC系。诱导产生的iPSC分化成心脏谱系。详细的全细胞膜片钳和细胞外多电极记录显示，与健康对照细胞相比，LQTS人iPSC衍生的心肌细胞（特征性LQTS表型）的动作电位持续时间显著延长。电压钳研究证实，这种动作电位时程延长源于心脏钾电流I-Kr的显着减少。重要的是，LQTS衍生的细胞也显示出显著的促心律失常性，其特征在于早期后去极化和触发的心律失常。然后，我们使用LQTS人iPSC衍生的心脏组织模型来评估现有和新型药理学药物的效力，这些药物可能加重（钾通道阻滞剂）或改善（钙通道阻滞剂，K-ATP通道开放剂和晚期钠通道阻滞剂）疾病表型。我们的研究说明了人类iPSC技术能够模拟遗传性心脏疾病的异常功能表型，并识别潜在的新治疗药物。因此，它代表了研究疾病机制，优化患者护理（个性化医疗）和帮助开发新疗法的有前途的范例。
The ability to generate patient-specific human induced pluripotent stem cells (iPSCs)(1-3) offers a new paradigm for modelling human disease and for individualizing drug testing(4). Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death(5-7). Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I-Kr. Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K-ATP-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.