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The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

ABSTRACT: The mammalian adult heart is a post-mitotic organ characterized by mainly polyploid cardiomyocytes (CMs). The post-mitotic status of polyploid adult CMs poses a clear limit to heart regeneration. Thus, understanding how polyploid CMs acquire this status is relevant to heart regeneration therapies. Here, we aim to unveil whether the PIDDosome, a multi-protein complex known to limit scheduled and accidental polyploidization events by activating p53, implements a CM-specific genetic program that controls CM polyploidization during heart development. Flow cytometric DNA content analysis coupled with image-based 3D volumetric measurements of CM nuclei showed that PIDDosome knockout animals harbor significantly more polyploid CMs compared to WT animals. This increased CM ploidy levels do not interfere with both cardiac structure and functional output in steady-state and is a cell-autonomous phenotype. During heart development, ploidy analyses revealed that the PIDDosome starts to shape CM ploidy status at postnatal day 7 (P7), reaching a plateau of its action at P14. Moreover, PIDDosome activation in CM is dependent on PIDD1 localization to the extra mother centrioles via the distal appendage protein ANKRD26. Interestingly, in opposite to prior observations the PIDDosome limits CM polyploidization in a p53-independent manner that still involves p21, as confirmed in genetic and nuclear RNAseq analysis. Together these results identify a new molecular machinery that controls proliferation of polyploid CMs postnatally, adding a set of new players that control the tightly regulated program of the terminal CM differentiation occurring in the postnatal heart.

ORGANISM(S): Mus musculus

PROVIDER: GSE275946 | GEO | 2026/01/20

REPOSITORIES: GEO

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Project description:BACKGROUND & AIMS: Thirty to ninety percent of hepatocytes contain whole genome duplications, making it imperative to understand the fates and functions of these polyploid cells and how they affect development of liver disease. An important question is how polyploid cells respond to chronic proliferative demands, which are characteristic of liver diseases, but a challenging situation for cells with multiple genomes. METHODS: To interrogate liver polyploidy, we employed a mouse with reversible ANLN ( Anillin actin binding protein) knockdown that drives hepatocyte polyploidization in a doxycycline inducible fashion. Diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) were used to induce chronic liver damage and hepatocellular carcinoma (HCC). We performed partial hepatectomies to test regeneration and RNA-seq to assess gene expression changes. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. In vivo imaging of mitotic hepatocytes estimated the frequency of aneuploidy during regeneration, and exome sequencing of 54 human cirrhotic nodules was used to quantify aneuploidy. RESULTS: Hepatocytes from mice given chronic CCl4 alone showed significant increases in ploidy. Super-polyploid mice with 97% polyploid hepatocytes, due to induced knockdown of Anln , were almost completely protected from tumorigenesis induced by DEN and chronic CCl4 . The protection was not associated with differences in regenerative capacity, tissue fitness, gene regulation, or mitotic errors. Regenerative contributions from a non-hepatocyte population were ruled out using lineage tracing, confirming that polyploids can replenish tissues during chronic damage. No lagging chromosomes or micronuclei were found in mitotic polyploid cells and there was no evidence of chromosomal copy number variations in 54 nodules, suggesting that aneuploidy is not a common outcome of polyploid cell divisions. CONCLUSION: During chronic injury, polyploid hepatocytes readily divide and regenerate while being buffered from tumor suppressor loss and tumorigenesis. Therapeutic strategies to increase numbers of polypoid hepatocytes could prevent cancer while preserving regeneration.

Project description:Loss of cardiomyocytes (CMs) following injury can lead to myocardial dysfunction, heart failure (HF) and ultimately death. The limited regenerative ability of the adult human heart after injury, however, poses a significant obstacle to restore cardiac function effectively. While mammalian hearts, including those of mice and humans, do have the potential to regenerate, this capacity is restricted to a narrow window during early stages of life. The molecular mechanisms governing the regenerative capacity of mammalian hearts remain incompletely understood. Exploring a comparative transcriptome analysis in regenerative neonatal vs. non-regenerative adult mouse CMs, we identified N-Cadherin, a member of Ca2+-dependent cell adhesion protein cadherin superfamily, as a potential novel regulator of CM proliferation/renewal. The primary objectives of this study were to elucidate the molecular mechanisms through which N-Cadherin regulates cardiomyocyte proliferation and regeneration, and to determine the therapeutic potential to promote CM renewal and restore cardiac function following injury by targeting N-Cadherin. Cardiac N-Cadherin expression exhibits a strong positive correlation with that of cell cycle- and proliferation-related genes. Its expression levels show an age-dependent reduction, with a 75% decrease of N-Cadherin in adult, compared to P1 neonatal, CMs. N-Cadherin expression is upregulated in the neonatal mouse heart in response to apical resection, especially in the peri-injury region, coinciding with increased CM mitotic activities in the neonatal heart. Knocking down N-Cadherin reduced, whereas overexpression of N-Cadherin increased, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, increased N-Cadherin potentiates CM renewal through direct binding with and stabilization of a pro-mitotic transcription regulator β-Catenin, leading to increased CMs proliferative activity. Deletion of β-Catenin-binding domain on N-Cadherin abrogated its pro-regenerative activity. Importantly, targeted depletion of N-Cadherin in CMs resulted in incomplete cardiac repair/regeneration and excessive fibrotic scar formation in neonatal mouse hearts following injury. Cardiac-specific overexpression of N-Cadherin in adult mouse heart using adeno-associated viral vectors, by contrast, resulted in increased CM proliferation and protected against myocardial infarction-induced adverse remodeling and contractile dysfunction. Adherent junction protein N-cadherin is demonstrated to play a crucial role in maintaining CM renewal potential by post-translational stabilization of β-Catenin. Enhancing N-cadherin expression levels and downstream signaling activities in the heart, therefore, could be a powerful new approach to promote cardiac regeneration and restore myocardial function in adult human heart following injury.

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The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

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