HCN4-overexpressing mouse embryonic stem cell-derived cardiomyocytes generate a new rapid rhythm in rats with bradycardia

Yukihiro Saito; Kazufumi Nakamura; Masashi Yoshida; Hiroki Sugiyama; Makoto Takano; Satoshi Nagase; Hiroshi Morita; Kengo F. Kusano; Hiroshi Ito

doi:10.1536/ihj.17-241

HCN4-overexpressing mouse embryonic stem cell-derived cardiomyocytes generate a new rapid rhythm in rats with bradycardia

Yukihiro Saito, Kazufumi Nakamura, Masashi Yoshida, Hiroki Sugiyama, Makoto Takano, Satoshi Nagase, Hiroshi Morita, Kengo F. Kusano, Hiroshi Ito

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN 4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 10³ mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

Original language	English
Pages (from-to)	601-606
Number of pages	6
Journal	International heart journal
Volume	59
Issue number	3
DOIs	https://doi.org/10.1536/ihj.17-241
Publication status	Published - May 2018

Keywords

Biological pacemaker
Cell therapy

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1536/ihj.17-241

Cite this

@article{40d04dda76dd4952a473bc3a85005544,

title = "HCN4-overexpressing mouse embryonic stem cell-derived cardiomyocytes generate a new rapid rhythm in rats with bradycardia",

abstract = "A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN 4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.",

keywords = "Biological pacemaker, Cell therapy",

author = "Yukihiro Saito and Kazufumi Nakamura and Masashi Yoshida and Hiroki Sugiyama and Makoto Takano and Satoshi Nagase and Hiroshi Morita and Kusano, {Kengo F.} and Hiroshi Ito",

note = "Funding Information: From the 1Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan, 2Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan, 3Department of Physiology, Kurume University School of Medicine, Kurume, Japan, 4Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan and 5Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. This study was supported by JSPS KAKENHI Grant Number 16K19407. Address for correspondence: Yukihiro Saito, MD, Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. E-mail: saitou-y@cc.okayama-u.ac.jp or Kazufumi Nakamura, MD. E-mail: i chibun@cc.okayama-u.ac.jp Received for publication April 27, 2017. Revised and accepted July 21, 2017. Released in advance online on J-STAGE April 6, 2018. doi: 10.1536/ihj.17-241 All rights reserved by the International Heart Journal Association. Publisher Copyright: {\textcopyright} 2018, International Heart Journal Association. All rights reserved.",

year = "2018",

month = may,

doi = "10.1536/ihj.17-241",

language = "English",

volume = "59",

pages = "601--606",

journal = "International Heart Journal",

issn = "1349-2365",

publisher = "International Heart Journal Association",

number = "3",

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TY - JOUR

T1 - HCN4-overexpressing mouse embryonic stem cell-derived cardiomyocytes generate a new rapid rhythm in rats with bradycardia

AU - Saito, Yukihiro

AU - Nakamura, Kazufumi

AU - Yoshida, Masashi

AU - Sugiyama, Hiroki

AU - Takano, Makoto

AU - Nagase, Satoshi

AU - Morita, Hiroshi

AU - Kusano, Kengo F.

AU - Ito, Hiroshi

N1 - Funding Information: From the 1Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan, 2Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan, 3Department of Physiology, Kurume University School of Medicine, Kurume, Japan, 4Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan and 5Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. This study was supported by JSPS KAKENHI Grant Number 16K19407. Address for correspondence: Yukihiro Saito, MD, Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. E-mail: saitou-y@cc.okayama-u.ac.jp or Kazufumi Nakamura, MD. E-mail: i chibun@cc.okayama-u.ac.jp Received for publication April 27, 2017. Revised and accepted July 21, 2017. Released in advance online on J-STAGE April 6, 2018. doi: 10.1536/ihj.17-241 All rights reserved by the International Heart Journal Association. Publisher Copyright: © 2018, International Heart Journal Association. All rights reserved.

PY - 2018/5

Y1 - 2018/5

N2 - A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN 4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

AB - A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN 4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

KW - Biological pacemaker

KW - Cell therapy

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JF - International Heart Journal

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ER -

HCN4-overexpressing mouse embryonic stem cell-derived cardiomyocytes generate a new rapid rhythm in rats with bradycardia

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