Format

Send to

Choose Destination
EMBO Mol Med. 2015 Apr;7(4):394-410. doi: 10.15252/emmm.201404757.

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

Author information

1
Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl r.passier@lumc.nl.
2
Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
3
Xention Ltd, Cambridge, UK.
4
Murdoch Childrens Research Institute Royal Children's Hospital, Melbourne, Vic., Australia.
5
Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium.
6
Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

Drugs targeting atrial-specific ion channels, Kv1.5 or Kir3.1/3.4, 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 Kir 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 Kv1.5 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 Kir3.1/3.4 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.

KEYWORDS:

COUP‐TF; arrhythmias; atrial cardiomyocytes; atrial fibrillation; ion channels

PMID:
25700171
PMCID:
PMC4403042
DOI:
10.15252/emmm.201404757
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center