Abstract
BackgroundCardiotoxicity remains an important concern in drug discovery. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have become an attractive platform to evaluate cardiotoxicity. However, the consistency between human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in prediction of cardiotoxicity has yet to be elucidated.MethodsHere we screened the toxicities of four representative drugs (E-4031, isoprenaline, quinidine, and haloperidol) using both hESC-CMs and hiPSC-CMs, combined with an impedance-based bioanalytical method.ResultsIt showed that both hESC-CMs and hiPSC-CMs can recapitulate cardiotoxicity and identify the effects of well-characterized compounds.ConclusionsThe combined platform of hPSC-CMs and an impedance-based bioanalytical method could improve preclinical cardiotoxicity screening, holding great potential for increasing drug development accuracy.
Highlights
Cardiotoxicity remains an important concern in drug discovery
Current in vitro cardiotoxicity screenings rely on the artificial expression of a single hERG channel in Chinese hamster ovary or human embryonic kidney cells, based on the two guidelines International Conference on Harmonization (ICH) S7B and ICH E14 [4, 5]
In combination with state-of-the-art bioanalytical methods, hESC-CMs have been reported as an alternative model for in vitro cardiotoxicity [6, 7]
Summary
Cardiotoxicity remains an important concern in drug discovery. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have become an attractive platform to evaluate cardiotoxicity. Methods: Here we screened the toxicities of four representative drugs (E-4031, isoprenaline, quinidine, and haloperidol) using both hESC-CMs and hiPSC-CMs, combined with an impedance-based bioanalytical method. Conclusions: The combined platform of hPSC-CMs and an impedance-based bioanalytical method could improve preclinical cardiotoxicity screening, holding great potential for increasing drug development accuracy. In combination with state-of-the-art bioanalytical methods, hESC-CMs have been reported as an alternative model for in vitro cardiotoxicity [6, 7]. Navarrete and colleagues [8] reported that hiPSC-CMs can recapitulate drug-induced arrhythmias. HESC-CMs and hiPSC-CMs have been reported possessing comparable ultrastructural features [9], their responses to identical compounds have not been systemically compared. The xCELLigence Real-Time Cell Analysis (RTCA) Cardio system, which utilizes impedance technology to quantify CM-beating properties, has been previously reported as an emerging method to quantify cardiac contractility [10]. We compared the capacity of hESC- and hiPSC-CMs for prediction of
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