Development of drug toxicity evaluation platform using hiPSC-derived cardiac organoids

IF 1.8 4区医学 Q4 PHARMACOLOGY & PHARMACY

Journal of pharmacological and toxicological methods Pub Date : 2025-09-01 DOI:10.1016/j.vascn.2025.107809

Hyun-lee Lee , Ji-hye Park , Hyun-su Kang , Ki-suk Kim

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引用次数: 0

Abstract

Cardiotoxicity is a critical aspect of safety evaluation in drug development. Traditional cardiotoxicity assessment methods rely primarily on animal models and 2D cell culture systems, which fail to replicate the complex physiological characteristics of human cardiac tissue fully. This study aims to generate human Cardiac Organoids (hCOs) derived from human induced Pluripotent Stem Cells (hiPSCs) and to use them to enhance the sensitivity of drug testing. hCOs were successfully cultured for up to 12 weeks, with a stable increase in heart rate observed over the cultivation period. Differentiation conditions were optimized by confirming the expression of cardiac markers (TNNT2), smooth muscle cell markers (aSMA), fibroblast markers (VIM), and endothelial markers (PECAM). The differentiation rate into cardiomyocytes was higher than that of conventional 2D cell culture methods. In calcium imaging using the positive drug nifedipine, the intensity of the calcium signal response of hCOs was confirmed to change depending on the concentration (1, 5, 10uM). This can be inferred that hCOs well reflects changes in various ion channels. Utilizing optimized hCOs conditions, we measured the changes in BPM induced by positive (Quinidine, Moxifloxacin, Nifedipine, E-4031), false positive (Diltiazem), false negative (Bepridil), and negative (Levofloxacin) drugs, comparing these to existing iCM data. The results demonstrated that hCOs exhibited more sensitive changes, suggesting that cardiac organoids can more sensitively and accurately reflect drug-induced cardiotoxicity than traditional 2D cell culture systems. This study presents a cardiotoxicity assessment platform using human-derived cardiac organoids. This approach can enhance the accuracy of cardiotoxicity assessment in the early stages of drug development, ultimately contributing to the development of safe and effective new drugs. Future research will measure electrophysiological changes to further optimize the evaluation platform and present an advanced cardiotoxicity evaluation platform.

This research was supported by a grant (22213MFDS391) from Ministry of Food and Drug Safety in 2024.

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hipsc源性心脏类器官药物毒性评价平台的建立

心脏毒性是药物开发中安全性评价的一个重要方面。传统的心脏毒性评估方法主要依赖于动物模型和二维细胞培养系统，无法完全复制人类心脏组织的复杂生理特征。本研究旨在利用人诱导多能干细胞（hiPSCs）制备人心脏类器官（hCOs），并利用其提高药物检测的敏感性。hco成功培养了12 周，在培养期间观察到心率稳定增加。通过确认心肌标记物（TNNT2）、平滑肌细胞标记物（aSMA）、成纤维细胞标记物（VIM）和内皮标记物（PECAM）的表达，优化分化条件。与传统的二维细胞培养方法相比，其向心肌细胞的分化率更高。在使用阳性药物硝苯地平的钙显像中，证实hCOs的钙信号响应强度随浓度（1,5,10 um）而变化。由此可以推断，hCOs很好地反映了各种离子通道的变化。利用优化的hCOs条件，我们测量了阳性（奎尼丁、莫西沙星、硝苯地平、E-4031）、假阳性（地尔硫卓）、假阴性（贝普利地尔）和阴性（左氧氟沙星）药物引起的BPM变化，并将其与现有的iCM数据进行比较。结果表明，hCOs表现出更敏感的变化，表明心脏类器官比传统的二维细胞培养系统更敏感、更准确地反映药物诱导的心脏毒性。本研究提出了一个使用人类来源的心脏类器官的心脏毒性评估平台。这种方法可以提高药物开发早期心脏毒性评估的准确性，最终有助于开发安全有效的新药。未来的研究将测量电生理变化，进一步优化评估平台，提出一个先进的心脏毒性评估平台。本研究于2024年获得国家食品药品安全部资助（22213MFDS391）。

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来源期刊

Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY

CiteScore

3.60

自引率

10.50%

发文量

审稿时长

26 days

期刊介绍： Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.