Abstract
Cardiomyocyte (CM) loss is a characteristic of various heart diseases, including ischaemic heart disease. Cardiac regeneration has been suggested as a promising strategy to address CM loss. Although many studies of regeneration have focused mainly on mononucleated or diploid CM, the limitations associated with the cytokinesis of polyploid and multinucleated CMs remain less well known. Here, we show that β-catenin, a key regulator in heart development, can increase cytokinesis in polyploid multinucleated CMs. The activation of β-catenin increases the expression of the cytokinesis-related factor epithelial cell transforming 2 (ECT2), which regulates the actomyosin ring and thus leads to the completion of cytokinesis in polyploid CMs. In addition, hypoxia can induce polyploid and multinucleated CMs by increasing factors related to the G1-S-anaphase of the cell cycle, but not those related to cytokinesis. Our study therefore reveals that the β-catenin can promote the cytokinesis of polyploid multinucleated CMs via upregulation of ECT2. These findings suggest a potential field of polyploid CM research that may be exploitable for cardiac regeneration therapy.
Highlights
Cardiomyocyte (CM) loss is a characteristic of various heart diseases, including ischaemic heart disease
We investigated the CM cell cycle in both groups and observed significant increases in phospho histone H3 Ser10 (pH3)+ CMs (Fig. 1j) in cyanotic tissues, compared to acyanotic tissues, whilst the groups did not exhibit significantly different numbers of aurora B+ CMs (Fig. 1k) and mklp2+ CMs (Fig. 1i)
These results suggest that systematic hypoxia may be responsible for the polyploidisation and multinucleation observed in CMs from cyanotic congenital heart disease (CHD) samples
Summary
Cardiomyocyte (CM) loss is a characteristic of various heart diseases, including ischaemic heart disease. The adult mammalian heart has a limited capacity for CM regeneration, and the subsequent replacement of lost tissue with functionally and electrically inert scar tissue leads to cardiac dysfunction and death[5,6,7] These characteristics have led to considerable research interest in the potential therapeutic simulation of CM proliferation. CM processes such as hypertrophic growth and DNA synthesis and repair have led many researchers to regard the adult mammalian heart as a pre-mitotic organ in which mitosis remains incomplete despite the presence of some cell cycle proteins and machinery[8] Within this pre-mitotic state, CMs are forced by multiple pro-hypertrophic factors to re-enter the cell cycle and undergo DNA synthesis in the absence of cytokinesis, leading to polyploidisation and multinucleation[9,10]. By elucidating the effects of β-catenin on polyploid CM cytokinesis, our study aims to provide information regarding the limitations of polyploid CM cytokinesis and potential therapeutic targets for cardiac regeneration
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