Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology
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 ca...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404757 |
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| author | Harsha D Devalla Verena Schwach John W Ford James T Milnes Said El‐Haou Claire Jackson Konstantinos Gkatzis David A Elliott Susana M Chuva de Sousa Lopes Christine L Mummery Arie O Verkerk Robert Passier |
| author_facet | Harsha D Devalla Verena Schwach John W Ford James T Milnes Said El‐Haou Claire Jackson Konstantinos Gkatzis David A Elliott Susana M Chuva de Sousa Lopes Christine L Mummery Arie O Verkerk Robert Passier |
| author_sort | Harsha D Devalla |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e5c077cf8cf042c9ae596c77921408ce |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e5c077cf8cf042c9ae596c77921408ce2025-08-24T11:44:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-02-017439441010.15252/emmm.201404757Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacologyHarsha D Devalla0Verena Schwach1John W Ford2James T Milnes3Said El‐Haou4Claire Jackson5Konstantinos Gkatzis6David A Elliott7Susana M Chuva de Sousa Lopes8Christine L Mummery9Arie O Verkerk10Robert Passier11Department of Anatomy & Embryology, Leiden University Medical CenterDepartment of Anatomy & Embryology, Leiden University Medical CenterXention LtdXention LtdXention LtdXention LtdDepartment of Anatomy & Embryology, Leiden University Medical CenterMurdoch Childrens Research Institute, Royal Children's HospitalDepartment of Anatomy & Embryology, Leiden University Medical CenterDepartment of Anatomy & Embryology, Leiden University Medical CenterHeart Failure Research Center, Academic Medical Center, University of AmsterdamDepartment of Anatomy & Embryology, Leiden University Medical CenterAbstract 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.https://doi.org/10.15252/emmm.201404757arrhythmiasatrial cardiomyocytesatrial fibrillationCOUP‐TFion channels |
| spellingShingle | Harsha D Devalla Verena Schwach John W Ford James T Milnes Said El‐Haou Claire Jackson Konstantinos Gkatzis David A Elliott Susana M Chuva de Sousa Lopes Christine L Mummery Arie O Verkerk Robert Passier Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology EMBO Molecular Medicine arrhythmias atrial cardiomyocytes atrial fibrillation COUP‐TF ion channels |
| title | Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology |
| title_full | Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology |
| title_fullStr | Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology |
| title_full_unstemmed | Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology |
| title_short | Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology |
| title_sort | atrial like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial selective pharmacology |
| topic | arrhythmias atrial cardiomyocytes atrial fibrillation COUP‐TF ion channels |
| url | https://doi.org/10.15252/emmm.201404757 |
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