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. Epub 2019 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / drug effects*
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Developmental / drug effects
  • Humans
  • Induced Pluripotent Stem Cells / drug effects*
  • Mice
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects*
  • Regeneration / drug effects
  • Regeneration / genetics
  • Small Molecule Libraries / pharmacology*

Substances

  • Small Molecule Libraries