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Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes

BACKGROUND: The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as...

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Autores principales: Saito, Yukihiro, Nakamura, Kazufumi, Yoshida, Masashi, Sugiyama, Hiroki, Akagi, Satoshi, Miyoshi, Toru, Morita, Hiroshi, Ito, Hiroshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973792/
https://www.ncbi.nlm.nih.gov/pubmed/35365232
http://dx.doi.org/10.1186/s13287-022-02818-y
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author Saito, Yukihiro
Nakamura, Kazufumi
Yoshida, Masashi
Sugiyama, Hiroki
Akagi, Satoshi
Miyoshi, Toru
Morita, Hiroshi
Ito, Hiroshi
author_facet Saito, Yukihiro
Nakamura, Kazufumi
Yoshida, Masashi
Sugiyama, Hiroki
Akagi, Satoshi
Miyoshi, Toru
Morita, Hiroshi
Ito, Hiroshi
author_sort Saito, Yukihiro
collection PubMed
description BACKGROUND: The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells. METHODS: Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared. RESULTS: HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and β adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs. CONCLUSIONS: Overexpression of HCN4 showed enhancement of I(f) current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-022-02818-y.
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spelling pubmed-89737922022-04-02 Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes Saito, Yukihiro Nakamura, Kazufumi Yoshida, Masashi Sugiyama, Hiroki Akagi, Satoshi Miyoshi, Toru Morita, Hiroshi Ito, Hiroshi Stem Cell Res Ther Research BACKGROUND: The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells. METHODS: Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared. RESULTS: HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and β adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs. CONCLUSIONS: Overexpression of HCN4 showed enhancement of I(f) current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-022-02818-y. BioMed Central 2022-04-01 /pmc/articles/PMC8973792/ /pubmed/35365232 http://dx.doi.org/10.1186/s13287-022-02818-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Saito, Yukihiro
Nakamura, Kazufumi
Yoshida, Masashi
Sugiyama, Hiroki
Akagi, Satoshi
Miyoshi, Toru
Morita, Hiroshi
Ito, Hiroshi
Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes
title Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes
title_full Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes
title_fullStr Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes
title_full_unstemmed Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes
title_short Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes
title_sort enhancement of pacing function by hcn4 overexpression in human pluripotent stem cell-derived cardiomyocytes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973792/
https://www.ncbi.nlm.nih.gov/pubmed/35365232
http://dx.doi.org/10.1186/s13287-022-02818-y
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