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中华细胞与干细胞杂志(电子版) ›› 2026, Vol. 16 ›› Issue (04) : 233 -239. doi: 10.3877/cma.j.issn.2095-1221.2026.04.006

综述

诱导多能干细胞分化的心肌细胞在遗传性原发性心律失常综合征模型中的研究进展
闫鸣琪, 向秋玲()   
  1. 510080 广州,中山大学中山医学院
  • 收稿日期:2025-09-04 出版日期:2026-08-01
  • 通信作者: 向秋玲

Advances in induced pluripotent stem cells-derived cardiomyocytes in inherited primary arrhythmia syndrome models

Mingqi Yan, Qiuling Xiang()   

  1. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
  • Received:2025-09-04 Published:2026-08-01
  • Corresponding author: Qiuling Xiang
引用本文:

闫鸣琪, 向秋玲. 诱导多能干细胞分化的心肌细胞在遗传性原发性心律失常综合征模型中的研究进展[J/OL]. 中华细胞与干细胞杂志(电子版), 2026, 16(04): 233-239.

Mingqi Yan, Qiuling Xiang. Advances in induced pluripotent stem cells-derived cardiomyocytes in inherited primary arrhythmia syndrome models[J/OL]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2026, 16(04): 233-239.

遗传性原发性心律失常综合征(IPAS)是一类由心脏离子通道或相关调节蛋白基因异常所致的疾病,通常伴有较高的心源性猝死风险。此类疾病临床表现谱广泛,可从无症状进展至晕厥、心律失常及传导障碍,甚至导致表型健康人群不明原因心源性猝死。诱导多能干细胞(iPSCs)以及iPSCs分化的心肌细胞(iPSC-CMs)为疾病模拟提供良好的体外疾病模型,它不仅有助于解析患者特异性疾病的机制,还避免动物模型的种属差异和人体组织样本的获取限制。本文简要介绍iPSCs以及iPSC-CMs的研究现状,并对长QT综合征、Brugada综合征、早复极综合征及儿茶酚胺敏感性多形性室性心动过速患者特异性iPSC-CMs的模型构建、药物筛选和机制研究等方面进展进行综述。

Inherited primary arrhythmia syndromes (IPAS) encompass a group of disorders stemming from genetic anomalies in cardiac ion channels or their regulatory proteins, frequently associated with an elevated risk of sudden cardiac death. These diseases manifest a broad spectrum of clinical presentations, ranging from asymptomatic states to syncope, arrhythmias, and conduction disturbances, potentially leading to unexplained sudden cardiac death in phenotypically healthy individuals. Induced pluripotent stem cells (iPSCs) and induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs) offer robust in vitro disease models. It not only helps to analyze the mechanism of patient-specific diseases, but also avoids species differences in animal models and restrictions on the acquisition of human tissue samples. This article briefly introduces the current research status of iPSCs and iPSC-CMs, and summarizes the progress in the construction of patient-specific iPSC-CMs models, drug screening, and mechanistic studies for long QT syndrome, Brugada syndrome, early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia.

图1 单层细胞诱导法分化iPSCs为心肌细胞注:iPSCs为诱导多能干细胞;iPSC-CMs为诱导多能干细胞分化的心肌细胞;CHIR99021为GSK-3β抑制剂,可激活Wnt/β-catenin信号通路。IWR-1和IWP2为Wnt信号通路的抑制剂,可抑制Wnt/β-catenin信号通路。它们的协作实现从iPSCs到心肌细胞的高效、可重复分化
表1 iPSCs在IPAS细胞模型中的应用
疾病名称 发表年份 创新点 参考文献
LQTS 2010 首次构建LQTS患者的iPSC-CMs,并发现其可以概括LQTS的电生理表型。 [25]
  2025 首次将hERG1的PAS结构域作为抗心律失常的治疗靶点,利用scFv2.10的单链抗体片段减少患者来源iPSC-CMs中心律失常事件的发生,发现治疗Jervell Lange-Nielsen综合征的新策略。 [26]
  2025 首次在兔模型中证实DHA-gly对LQT2的电生理改善作用,同时也在iPSC-CMs中揭示其不良效应。这一发现提示iPSC-CMs可作为筛选平台,在早期评估候选药物对心肌收缩功能的不良影响。 [27]
  2024 美西律可改善LQT2-iPSC-CMs、LQT2兔模型和多数LQT2患者的心脏异常复极化,具有抗心律失常功效。对于高危LQT2患者,应在常规治疗中加入美西律。 [28]
  2026 构建一个将患者来源iPSC-CMs、微电极阵列与机器学习相结合的心脏毒性预测平台。使用LQTS和BrS患者来源的iPSC-CMs作为提供患者真实遗传背景和电生理表型的功能模型,微电极阵列记录的数据直接用于训练和验证机器学习模型,从而实现药物安全性评估。 [29]
BrS 2016 首次建立BrS-iPSC-CMs模型,并证明BrS-iPSC-CMs电生理表型异常与SCN5A变异有关。 [36]
  2023 患者特异性iPSC-CMs可以重现BrS不同表型的严重程度,保留钙电流可能是无症状突变携带者抵抗BrS心律失常发生的机制。 [37]
  2025 利用CRISPR/Cas9技术在iPSCs中引入SCN5A的罕见非编码变异,分化成心肌细胞,发现该变异破坏高度保守的MEF2转录因子结合位点导致SCN5A表达下降和钠电流密度降低,证明其致病性。 [38]
  2025 发现发热与炎症对BrS的影响具有基因型特异性,为未来根据基因型进行个体化临床管理提供重要依据。 [39]
  2024 利用iPSC-CMs模型展示了检测心肌细胞电生理和机械性能的创新平台。该平台不仅能检测体外模型的疾病特征,还能评估其对药物的反应,作为临床和药理学研究的工具具有可行性。 [40]
ERS 2021 多基因突变的患者在触电后心电图出现ERS和短QT综合征的特征,其iPSC-CMs表现出钙瞬变异常、APD缩短、INa密度降低和IK-ATP通道增强等异常电生理现象。 [45]
  2024 DPP6突变的患者特异性iPSC-CMs显示更长的APD和更大的Ito密度,且基因编辑证明这些电生理异常与DPP6突变有关。 [46]
CPVT 2023 CALM2p.E46K突变CPVT患者的iPSC-CMs表现出钙调蛋白与RyR2亲和力增加。 [50]
  2021 在CPVT小鼠和CPVT-iPSC-CMs中验证了筛选出的药物双硫仑和依折麦布可抑制心律失常的发生。 [51]
  2025 利用CRISPR/Cas9基因编辑技术在iPSC-CMs中研究了CPVT1相关的2个RyR2新突变对钙信号的影响,发现不同位点突变可导致迥异的钙信号表型。 [52]
  2022 CPVT1患者特异性iPSC-CMs证明RYR2三种新型变异的致病性,并验证纳多洛尔和氟卡尼的疗效。 [53]
  2025 建立一种同时记录心肌细胞动作电位与钙瞬变的新型光学检测方法,发现CPVT患者特异性iPSC-CMs中,KN-93能高效改善钙瞬变异常且不影响动作电位形态。 [54]
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[14] 阎凯, 付雍, 章正涛, 卢文峰, 王毅州, 巫国谊, 张海斌. 中晚期肝癌疗效预测模型暨肝癌类器官模型研究进展[J/OL]. 中华肝脏外科手术学电子杂志, 2023, 12(03): 348-351.
[15] 张津, 徐如祥. 脊髓类器官研究进展:从基础构建到疾病建模与再生修复[J/OL]. 中华神经创伤外科电子杂志, 2026, 12(02): 65-72.
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