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

(2015) EMBO MOLECULAR MEDICINE. 7(4). p.394-410
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Abstract
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.
Keywords
COUP-TF, RECTIFIER K+ CURRENT, ion channels, atrial fibrillation, atrial cardiomyocytes, arrhythmias, RETINOIC-ACID, COUP-TFII, DEVELOPMENTAL EXPRESSION, FIBRILLATION, DIFFERENTIATION, MYOCYTES, ACETYLCHOLINE, ACTIVATION, GUIDELINES

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Citation

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Chicago
Devalla, Harsha D, Verena Schwach, John W Ford, James T Milnes, Said El-Haou, Claire Jackson, Konstantinos Gkatzis, et al. 2015. “Atrial-like Cardiomyocytes from Human Pluripotent Stem Cells Are a Robust Preclinical Model for Assessing Atrial-selective Pharmacology.” Embo Molecular Medicine 7 (4): 394–410.
APA
Devalla, H. D., Schwach, V., Ford, J. W., Milnes, J. T., El-Haou, S., Jackson, C., Gkatzis, K., et al. (2015). Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology. EMBO MOLECULAR MEDICINE, 7(4), 394–410.
Vancouver
1.
Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, Jackson C, et al. Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology. EMBO MOLECULAR MEDICINE. 2015;7(4):394–410.
MLA
Devalla, Harsha D et al. “Atrial-like Cardiomyocytes from Human Pluripotent Stem Cells Are a Robust Preclinical Model for Assessing Atrial-selective Pharmacology.” EMBO MOLECULAR MEDICINE 7.4 (2015): 394–410. Print.
@article{7017588,
  abstract     = {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.},
  author       = {Devalla, Harsha D and Schwach, Verena and Ford, John W and Milnes, James T and El-Haou, Said and Jackson, Claire and Gkatzis, Konstantinos and Elliott, David A and Chuva de Sousa Lopes, Susana Marina and Mummery, Christine L and Verkerk, Arie O and Passier, Robert},
  issn         = {1757-4676},
  journal      = {EMBO MOLECULAR MEDICINE},
  keywords     = {COUP-TF,RECTIFIER K+ CURRENT,ion channels,atrial fibrillation,atrial cardiomyocytes,arrhythmias,RETINOIC-ACID,COUP-TFII,DEVELOPMENTAL EXPRESSION,FIBRILLATION,DIFFERENTIATION,MYOCYTES,ACETYLCHOLINE,ACTIVATION,GUIDELINES},
  language     = {eng},
  number       = {4},
  pages        = {394--410},
  title        = {Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology},
  url          = {http://dx.doi.org/10.15252/emmm.201404757},
  volume       = {7},
  year         = {2015},
}

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