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

EMBO Molecular Medicine

Harsha D Devalla⁴  Verena Schwach⁴  John W Ford¹  James T Milnes¹  Said El-Haou¹  Claire Jackson¹  Konstantinos Gkatzis⁴  David A Elliott³  Susana M Chuva de Sousa Lopes⁴  Christine L Mummery⁴  Arie O Verkerk² 

[1] Xention Ltd, Cambridge, UK;Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Vic., Australia;Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands

关键词: arrhythmias;    atrial cardiomyocytes;    atrial fibrillation;    COUP‐TF;    ion channels;   

DOI  :  10.15252/emmm.201404757

来源: Wiley

【 摘 要 】

Abstract

Drugs targeting atrial-specific ion channels, K_v1.5 or K_ir3.1/3.4, 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_v1.5 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_ir3.1/3.4 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.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.