Journal Article

Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology

Verkerk, Arie O, Schwach, Verena, El‐Haou, Said, Elliott, David A, Devalla, Harsha D, Chuva de Sousa Lopes, Susana M, Jackson, Claire, Gkatzis, Konstantinos, Ford, John W, Mummery, Christine L, Passier, Robert, Milnes, James T

2015

Overview

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 (hESC)‐derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial‐like (hESC‐atrial) and ventricular‐like (hESC‐ventricular) CMs. We found the expression of atrial‐specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding K ir 3.1), in hESC‐atrial CMs 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, hESC‐atrial but not hESC‐ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC‐atrial CMs, XEN‐R0703, a novel K ir 3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN‐R0703 had an effect on hESC‐ventricular CMs. In summary, we demonstrate that hESC‐atrial CMs are a robust model for pre‐clinical testing to assess atrial selectivity of novel antiarrhythmic drugs. Synopsis Newly generated human embryonic stem cell‐derived atrial‐like cardiomyocytes resemble human atrial cardiomyocytes and prove to be a valuable model for pre‐clinical drug screenings to identify effective atrial‐selective compounds against atrial fibrillation. Exogenous addition of retinoic acid drives differentiating human embryonic stem cells towards atrial‐like cardiomyocytes. COUP‐TFI and COUP‐TFII are induced during atrial differentiation. COUP‐TF transcription factors regulate atrial‐specific ion channel genes. hESC‐atrial CMs respond to drugs targeting atrial‐selective ion channels. Graphical Abstract Newly generated human embryonic stem cell‐derived atrial‐like cardiomyocytes resemble human atrial cardiomyocytes and prove to be a valuable model for pre‐clinical drug screenings to identify effective atrial‐selective compounds against atrial fibrillation.

• Publisher: Nature Publishing Group UK,EMBO Press,BlackWell Publishing Ltd,Springer Nature
• Subject: Action potential / Animal models / Arrhythmia / arrhythmias / atrial cardiomyocytes / atrial fibrillation / Atrial Fibrillation - drug therapy / Atrial Fibrillation - metabolism / Atrial Fibrillation - pathology / Cardiac arrhythmia / Cardiomyocytes / Cell culture / Cell lines / COUP‐TF / Data analysis / Drug delivery / Drug Delivery Systems - methods / Drug Evaluation, Preclinical - methods / Drugs / EMBO04 / EMBO28 / EMBO39 / Experiments / Fibrillation / Flow cytometry / G Protein-Coupled Inwardly-Rectifying Potassium Channels - antagonists & inhibitors / G Protein-Coupled Inwardly-Rectifying Potassium Channels - biosynthesis / Gene Expression / Genes / Heart / Heart Atria - metabolism / Heart Atria - pathology / Humans / Ion channels / Kv1.5 Potassium Channel - antagonists & inhibitors / Kv1.5 Potassium Channel - biosynthesis / Models, Biological / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Pharmaceutical industry / Pharmacology / Physiology / Pluripotency / Pluripotent Stem Cells - metabolism / Pluripotent Stem Cells - pathology / Potassium Channel Blockers - pharmacology / Potassium channels (inwardly-rectifying) / Potassium channels (voltage-gated) / R&D / Research & development / Research Article / Retinoic acid / Stem cell transplantation / Stem cells / Transcription factors / Ventricle