Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of β-catenin

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.

Dynamic map illuminates Hippo to cMyc module crosstalk driving cardiomyocyte proliferation

“…Our cytokinesis module relies on nodes and interactions that have been primarily studied in other cell types. This included those examined in CM regulation, such as anillin, shown by Engel et al as a critical process for cytokinesis in cardiomyocytes, and Ect2, shown to contribute to cytokinesis and increased binucleated cells ( Figure 1D ) (Bergmann, 2021; Engel et al, 2006; Jiang et al, 2019; Liu et al, 2019). Extracellular factors have been identified to activate intracellular receptors involved in cardiomyocyte proliferation: FGF1, Nrg1, and IGF1 (Rebouças et al, 2016).…”

Detection of mitotic neuroblasts provides additional evidence of steady state neurogenesis in the adult small intestinal myenteric plexus

“…Adult murine small intestinal myenteric ganglia show evidence of cell proliferation. By using antibodies against the protein phospho-Histone H3 (pH3; phosphorylated at residue Ser10, Sigma), a widely accepted marker for DNA synthesis and cell proliferation [9][10][11][12][13] , in conjunction with . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…Adult murine small intestinal myenteric ganglia show evidence of cell proliferation. By using antibodies against the protein phospho-Histone H3 (pH3; phosphorylated at residue Ser10, Sigma), a widely accepted marker for DNA synthesis and cell proliferation [9][10][11][12][13] , in conjunction with ANNA-1 antisera against the pan-neuronal marker Hu, we observed that the adult healthy small intestinal LM-MP tissue contains diverse cell populations of pH3 immunostained cells that are present both within and outside of the myenteric ganglia (Fig 1 a, b). Importantly, the pH3-positive, intra-ganglionic cell population comprises of Hu-immunostained neurons, as well as other unlabeled cells that we assume to be populations of proliferating enteric glial cells 14 and enteric neuronal precursor cells, that we have previously shown to express Nestin and Ki-67 7 .…”

Transcriptional regulation of mammalian heart regeneration

“…Therefore, Wnt/β-catenin signalling could maintain the regenerative metabolic ground-state whilst other pro-proliferative factors (such as Hippo/Yap or neuregulin) drive cardiomyocyte mitosis. In support of this hypothesis, it was recently shown that β-catenin only drives adult cardiomyocyte proliferation if animals are housed in hypoxic conditions (Jiang et al, 2019). Hence, loss of β-catenin signalling during postnatal maturation and the acquisition of mature metabolic programs could represent a fundamental regenerative block in the adult mammalian heart.…”

“…Patterson and colleagues made the surprising discovery that different mouse strains exhibited variable levels of cardiac regeneration which was correlated with the proportion of mononuclear diploid cardiomyocytes (Patterson et al, 2017). Moreover, multinucleation and polyploidisation is associated with downregulation of cytokinetic genes (Jiang et al, 2019;Leone et al, 2018;. Observations such as these have led to the hypothesis that polyploidisation directly prohibits cardiomyocyte proliferation.…”