Somatic polyploidy (more than diploid content of the genome) usually arises during organogenesis, tissue repair, and age-associated disease. How somatic polyploidy is achieved and affects cell function is highly cell type-specific and context-dependent. In the heart, cardiomyocyte polyploidy is prevalent across mammals. Shortly after birth, rodent cardiomyocytes lose the ability to complete cytokinesis and become polyploid. This transition coincides with cardiomyocyte maturation and cell cycle exit, and is one of the key determinants of the poor regenerative capacity of the mammalian heart (Patterson et al., 2017; Gonzales-Rosa et al., 2018). Similarly, injury-induced cell cycle activity in adult rodent and human cardiomyocytes usually results in increase in ploidy but not cytokinesis, which may account for their lack of regeneration.
Despite its importance in heart physiology, HOW and WHY mammalian cardiomyocytes become polyploid is poorly understood. The goal of our lab is to understand:
(a) How cardiomyocyte polyploidy is regulated?
(b) How polyploidy influences cardiomyocyte function and regeneration?
REGULATORY MECHANISMS OF CARDIOMYOCYTE POLYPLOIDY?
We are interested in understanding how mammalian cardiomyocytes become polyploid. In our previous study (Wu et al., 2020), we showed that both cell-autonomous and non-autonomous factors are influencing cardiomyocyte polyploidization.
Currently, we are investigating:
the transcriptional control of postnatal cardiomyocyte polyploidization
how signaling mechanisms (intracellular and intercellular) that modulate cardiomyocyte polyploidization?
can these factors promote adult cardiomyocyte renewal and heart regeneration?
Why do mammalian cardiomyocytes become polyploid? Naturally-occurring cardiomyocyte diploidy in mouse hearts do not exceed 15 - 20%. This observation suggest that polyploidy is required for postnatal cardiomyocyte maturation and/or function.
Many questions remain: (a) what are the fundamental difference between diploid and polyploid cardiomyocytes? (b) what is the functional significance for polyploid cardiomyocytes? (c) are there advantages or limitations between different modes of polyploidization (multinucleation in rodents vs mononuclear polyploid in humans?)
We have generated different tools to investigate the impact of polyploidy at the cellular and organ levels.