Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes

  • J Mol Cell Cardiol. 2019 Mar;128:90-95. doi: 10.1016/j.yjmcc.2019.01.020.
Masamichi Ito  1 ,  Hironori Hara  1 ,  Norifumi Takeda  1 ,  Atsuhiko T Naito  2 ,  Seitaro Nomura  1 ,  Masaki Kondo  3 ,  Yutaka Hata  4 ,  Masanobu Uchiyama  5 ,  Hiroyuki Morita  1 ,  Issei Komuro  6
Affiliations
  • 1. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
  • 2. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ohta-ku, Tokyo, Japan.
  • 3. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Tokyo, Japan.
  • 4. Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan.
  • 5. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Tokyo, Japan; Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry Laboratory, RIKEN, 2-1, Hirosawa, Wako-city, Saitama, Japan.
  • 6. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Electronic address: [email protected].
PMID: 30684499 DOI: 10.1016/j.yjmcc.2019.01.020
Abstract

Background: Since regenerative capacity of adult mammalian myocardium is limited, activation of the endogenous proliferative capacity of existing cardiomyocytes is a potential therapeutic strategy for treating heart diseases accompanied by cardiomyocyte loss. Recently, we performed a compound screening and developed a new drug named TT-10 (C11H10FN3OS2) which promotes the proliferation of murine cardiomyocytes via enhancement of YES-associated protein (YAP)-transcriptional enhancer factor domain (TEAD) activity and improves cardiac function after myocardial infarction in adult mice.

Methods and results: To test whether TT-10 can also promote the proliferative capacity of human cardiomyocytes, we investigated the efficacy of TT-10 on human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSCMs). The hiPSCs were established from monocytes obtained from healthy donors and cardiac differentiation was performed using a chemically defined protocol. As was observed in murine cardiomyocytes, TT-10 markedly promoted cell cycle activation and increased cell division of hiPSCMs. We then evaluated Other effects of TT-10 on the functional properties of hiPSCMs by gene expression and cell motion analyses. We observed that TT-10 had no unfavorable effects on the expression of functional and structural genes or the contractile properties of hiPSCMs.

Conclusions: Our results suggest that the novel drug TT-10 effectively activated the cell cycle of hiPSCMs without apparent functional impairment of myocardium, suggesting the potential of clinical usefulness of this drug.

Keywords
Cell cycle activation; Hippo pathway; Induced pluripotent stem cell-derived cardiomyocyte; Regeneration; Regenerative medicine; Small molecule.
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