Open AccessAtrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology
Author(s) -
Devalla Harsha D,
Schwach Verena,
Ford John W,
Milnes James T,
ElHaou Said,
Jackson Claire,
Gkatzis Konstantinos,
Elliott David A,
Chuva de Sousa Lopes Susana M,
Mummery Christine L,
Verkerk Arie O,
Passier Robert
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404757
Subject(s) - retinoic acid , induced pluripotent stem cell , atrial fibrillation , pharmacology , embryonic stem cell , repolarization , medicine , cardiology , electrophysiology , chemistry , gene , biochemistry
Drugs targeting atrial‐specific ion channels, K v 1.5 or K ir 3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non‐cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte ( CM ). In the current study, we tested whether human embryonic stem cell (h ESC )‐derived atrial CM s could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during h ESC differentiation, we generated atrial‐like (h ESC ‐atrial) and ventricular‐like (h ESC ‐ventricular) CM s. We found the expression of atrial‐specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding K ir 3.1), in h ESC ‐atrial CM s and further demonstrated that these ion channel genes are regulated by COUP‐TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and K v 1.5 blocker, XEN ‐D0101, h ESC ‐atrial but not h ESC ‐ventricular CM s showed action potential ( AP ) prolongation due to a reduction in early repolarization. In h ESC ‐atrial CM s, XEN ‐R0703, a novel K ir 3.1/3.4 blocker restored the AP shortening caused by CC h. Neither CC h nor XEN ‐R0703 had an effect on h ESC ‐ventricular CM s. In summary, we demonstrate that h ESC ‐atrial CM s are a robust model for pre‐clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.