Intrinsic regulations of cardiomyocyte polyploidization In rodents, cardiomyocytes lose the ability to complete cytokinesis and become polyploid during the first week of birth. This transition coincides with postnatal cardiomyocyte maturation, which is characterized by a series of transcriptional and post-transcriptional changes. To elucidate the underlying molecular mechanisms, we compared the transcriptome between cycling neonatal (cytokinesis-competent) and postnatal (cytokinesis-incompetent) mouse cardiomyocytes. Through these and other analyzes, we have identified many interesting candidate genes that might inhibit or promote cardiomyocyte cytokinesis. We will 1) investigate the function of these candidates in cardiomyocyte polyploidization, and 2) manipulate their function to promote cardiac repair in adult mammals after injury.
Extrinsic regulations of cardiomyocyte polyploidization In addition to intrinsic changes, cardiomyocyte polyploidization is also influenced by external factors including the extracellular matrix (ECM) and other non-myocytes cardiac cell types. We have previously identified a key role for the ECM in regulating cardiomyocyte cytokinesis (Wu et al., 2020 Circ Res); proteomic analysis further identified matrisome proteins (i.e., ECM or ECM-associated proteins) that can potentially promote or inhibit cardiomyocyte cytokinesis. One exciting candidate is Slit2, which plays important roles in axon guidance and angiogenesis. We are currently investigating the role and the molecular mechanisms of Slit signaling in cardiomyocyte polyploidization. In addition, we are also studying how cardiomyocyte-endothelial crosstalk influences cardiomyocyte polyploidy.
Ploidy and cell/organ physiology Somatic polyploidy serves important functions during development, homeostasis, and disease. However, how ploidy influences cell/organ function is highly cell type-specific and context-dependent. Using a variety of existing and new in vitro and in vivo tools that enable the manipulation of ploidy in cell type of interest, we will investigate the significance of polyploidy under physiological and pathological conditions.