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

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.