Evaluation of in vitro models of stem cell-derived cardiomyocytes to screen for potential cardiotoxicity of chemicals. (September 2020)

• Record Type: Journal Article
• Authors: Shi, Miaoying; Tien, Nguyen T.; de Haan, Laura; Louisse, Jochem; Rietjens, Ivonne M.C.M.; Bouwmeester, Hans
• Is Part Of: Toxicology in vitro. Volume 67(2020)
• Publication Date: 2020-09
• Subjects: Cardiotoxicity -- Human induced pluripotent stem cell-derived cardiomyocytes -- Mouse embryonic stem cell-derived cardiomyocytes -- Multi-electrode array -- Clinical data; AIC Akaike's Information Criterion -- AMP10 concentration causing 10% reduction in sodium spike amplitude -- BPM beats per minute -- BMC benchmark concentration -- BMD benchmark dose -- BR10 concentration causing 10% increase in beating rate -- DMSO dimethyl sulfoxide -- ECG electrocardiogram -- fu unbound fraction -- FPD field potential duration -- FPDc corrected field potential duration -- FPDc10 concentration inducing 10% prolongation of FPDc -- -FPDc10 concentration shortening FPDc by 10% -- hECG10 human plasma concentrations corresponding to 10% change in the ECG -- hERG human ether-a-go-go related gene -- hiPSC-CMs human induced pluripotent stem cell-derived cardiomyocytes -- MEA multi-electrode array -- mESC-CMs mouse embryonic stem cell-derived cardiomyocytes; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2020.104891
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Cardiotoxicity is an important toxicological endpoint for chemical and drug safety assessment. The present study aims to evaluate two stemcell-based in vitro models for cardiotoxicity screening of chemicals. Eleven model compounds were used to evaluate responses of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) using beating arrest as a readout and the analysis of electrophysiological parameters measured with a multi-electrode array (MEA) platform of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results revealed that the hiPSC-CM MEA assay responded to all compounds. The mESC-CM beating arrest assay was not responsive to potassium channel blockers and showed a lower sensitivity to sodium channel blockers and Na + /K + ATPase inhibitors compared to the hiPSC-CM MEA assay. Calcium channel blockers and a β-adrenergic receptor agonist showed comparable potencies in both models. The in vitro response concentrations from hiPSC-CMs were highly concordant with human effective serum concentrations of potassium and sodium channel blockers. It is concluded that both in vitro models enable the cardiotoxicity screening with different applicability domains. The mESC-CM beating arrest assay may be used as a first step in a tiered approach while the hiPSC-CM MEA assay may be the best starting point for quantitative in vitro to in vivo extrapolations. Highlights: Mouse and human stem cell-based in vitro models for cardiotoxicity were evaluated. The in vitro models show mode-of-action dependent differences in sensitivity. The in vitro hiPSC-CMs responses correlate well with human clinical data. hiPSC-CM MEA assay can be a basis for quantitative in vitro in vivo extrapolation.