Dynamic monitoring of beating periodicity of stem cell-derived cardiomyocytes as a predictive tool for preclinical safety assessment
Dynamic monitoring of beating periodicity of stem cell-derived cardiomyocytes as a predictive tool for preclinical safety assessment
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DOI：
10.1111/j.1476-5381.2011.01623.x
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发表时间：
2012-03-01
影响因子：
7.3
通讯作者：
Xu, Xiao
中科院分区：
文献类型：
--
作者：
Abassi, Yama A.;Xi, Biao;Xu, Xiao
背景和目的心脏毒性是药物开发中的一个主要问题，因此必须在药物发现过程的早期对临床候选药物进行彻底的不良反应测试。在本报告中，我们研究了基于阻抗的微电子检测系统与小鼠胚胎干细胞衍生的心肌细胞结合用于评估药物发现过程中的化合物风险的效用。实验方法通过最近开发的基于微电子的系统使用阻抗读数来测量心肌细胞的跳动。我们使用小鼠干细胞来源的心肌细胞获得了 60 多种化合物的剂量反应曲线，包括离子通道调节剂、变时性/促离子剂、hERG 运输抑制剂和已知可诱发尖端扭转型室性心动过速心律失常的药物。 主要结果 该系统灵敏且定量地检测了心脏功能调节剂的作用，包括一些电生理学遗漏的化合物。促心律失常化合物产生反映心律失常的特征谱，其可用于鉴定其他促心律失常化合物。时间序列数据可用于识别通过复杂机制（例如抑制 hERG 通道运输）诱发心律失常的化合物。此外，时间分辨率允许评估同时影响心肌细胞搏动和活力的化合物。结论和意义干细胞源性心肌细胞搏动的微电子监测提供了高通量、定量和预测性测定系统，可用于在药物发现过程的早期评估心脏责任。干细胞技术与微电子监测的融合应有助于心脏安全评估。
BACKGROUND AND PURPOSECardiac toxicity is a major concern in drug development and it is imperative that clinical candidates are thoroughly tested for adverse effects earlier in the drug discovery process. In this report, we investigate the utility of an impedance-based microelectronic detection system in conjunction with mouse embryonic stem cell-derived cardiomyocytes for assessment of compound risk in the drug discovery process.EXPERIMENTAL APPROACHBeating of cardiomyocytes was measured by a recently developed microelectronic-based system using impedance readouts. We used mouse stem cell-derived cardiomyocytes to obtain dose-response profiles for over 60 compounds, including ion channel modulators, chronotropic/ ionotropic agents, hERG trafficking inhibitors and drugs known to induce Torsades de Pointes arrhythmias.KEY RESULTSThis system sensitively and quantitatively detected effects of modulators of cardiac function, including some compounds missed by electrophysiology. Pro-arrhythmic compounds produced characteristic profiles reflecting arrhythmia, which can be used for identification of other pro-arrhythmic compounds. The time series data can be used to identify compounds that induce arrhythmia by complex mechanisms such as inhibition of hERG channels trafficking. Furthermore, the time resolution allows for assessment of compounds that simultaneously affect both beating and viability of cardiomyocytes.CONCLUSIONS AND IMPLICATIONSMicroelectronic monitoring of stem cell-derived cardiomyocyte beating provides a high throughput, quantitative and predictive assay system that can be used for assessment of cardiac liability earlier in the drug discovery process. The convergence of stem cell technology with microelectronic monitoring should facilitate cardiac safety assessment.