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 Itoh

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)601-606
Number of pages6
JournalInternational Heart Journal
Volume59
Issue number3
DOIs
Publication statusPublished - May 1 2018

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Bradycardia
Cardiac Myocytes
Biological Clocks
Ventricular Premature Complexes
Atrioventricular Block
Artificial Pacemaker
Telemetry
Mouse Embryonic Stem Cells
Electromagnetic Phenomena
Cell Transplantation
Lactic Acid
Animal Models
Rabbits
Glucose
Infection
Serum
Genes

Keywords

  • Biological pacemaker
  • Cell therapy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

HCN4-overexpressing mouse embryonic stem cell-derived cardiomyocytes generate a new rapid rhythm in rats with bradycardia. / Saito, Yukihiro; Nakamura, Kazufumi; Yoshida, Masashi; Sugiyama, Hiroki; Takano, Makoto; Nagase, Satoshi; Morita, Hiroshi; Kusano, Kengo F.; Itoh, Hiroshi.

In: International Heart Journal, Vol. 59, No. 3, 01.05.2018, p. 601-606.

Research output: Contribution to journalArticle

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