Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG

Jonsson, Malin K.B.; Vos, Marc A.; Mirams, Gary R.; Duker, G�ran; Sartipy, Peter; De Boer, Teun P.; Van Veen, Toon A.B.

Abstract

Human embryonic stem cell-derived cardiomyocytes (hESC-CM) have been proposed as a new model for safety pharmacology. So far, a thorough description of their basic electrophysiology and extensive testing, and mechanistic explanations, of their overall pro-arrhythmic ability is lacking. Under standardized conditions, we have evaluated the sensitivity of hESC-CM to proarrhythmic provocations by blockade of hERG and other channels. Using voltage patch clamp, some ion current densities (pA/pF) in hESC-CM were comparable to adult CM: I Kr (-12.5±6.9), I Ks (0.65±0.12), I Na,peak (-72±21), I Na,late (-1.10±0.36), and I Ca,L (-4.3±0.6). I f density was larger (-10±1.1) and I K1 not existent or very small (-2.67±0.3). The low I K1 density was corroborated by low KCNJ2 mRNA levels. Effects of pro-arrhythmic compounds on action potential (AP) parameters and provocation of early afterdepolarizations (EADs) revealed that Chromanol293B (100μmol/l) and Bay K8644 (1μmol/l) both significantly prolonged APD 90. ATX-II (

Citation

Jonsson, M. K., Vos, M. A., Mirams, G. R., Duker, G., Sartipy, P., De Boer, T. P., & Van Veen, T. A. (2012). Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. Journal of Molecular and Cellular Cardiology, 52(5), 998-1008. https://doi.org/10.1016/j.yjmcc.2012.02.002

• Journal Article Type: Article
• Acceptance Date: Feb 3, 2012
• Online Publication Date: Feb 13, 2012
• Publication Date: May 1, 2012
• Deposit Date: Jan 14, 2020
• Journal: Journal of Molecular and Cellular Cardiology
• Print ISSN: 0022-2828
• Electronic ISSN: 1095-8584
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 52
• Issue: 5
• Pages: 998-1008
• DOI: https://doi.org/10.1016/j.yjmcc.2012.02.002
• Public URL: https://nottingham-repository.worktribe.com/output/3217604
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0022282812000843