Polyploidization in liver tissue.

International audiencePolyploidy (alias whole genome amplification) refers to organisms containing more than two basic sets of chromosomes. Polyploidy was first observed in plants more than a century ago, and it is known that such processes occur in many eukaryotes under a variety of circumstances. In mammals, the development of polyploid cells can contribute to tissue differentiation and, therefore, possibly a gain of function; alternately, it can be associated with development of disease, such as cancer. Polyploidy can occur because of cell fusion or abnormal cell division (endoreplication, mitotic slippage, or cytokinesis failure). Polyploidy is a common characteristic of the mammalian liver. Polyploidization occurs mainly during liver development, but also in adults with increasing age or because of cellular stress (eg, surgical resection, toxic exposure, or viral infections). This review will explore the mechanisms that lead to the development of polyploid cells, our current state of understanding of how polyploidization is regulated during liver growth, and its consequence on liver function

Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma

BACKGROUND & AIMS Mcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1$^{Δhep}$) on hepatocyte ploidy and cell cycle in murine liver in vivo and the possible implications on HCC. METHODS Livers of young Mcl-1$^{Δhep}$ and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, in situ chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression in vivo. Mcl-1$^{Δhep}$ tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing. RESULTS In young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1$^{Δhep}$ tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology. CONCLUSIONS Our study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes in vivo. In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer. IMPACT AND IMPLICATIONS Although Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes in vivo, whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation

Separase: a universal trigger for sister chromatid disjunction but not chromosome cycle progression

Separase is a protease whose liberation from its inhibitory chaperone Securin triggers sister chromatid disjunction at anaphase onset in yeast by cleaving cohesin's kleisin subunit. We have created conditional knockout alleles of the mouse Separase and Securin genes. Deletion of both copies of Separase but not Securin causes embryonic lethality. Loss of Securin reduces Separase activity because deletion of just one copy of the Separase gene is lethal to embryos lacking Securin. In embryonic fibroblasts, Separase depletion blocks sister chromatid separation but does not prevent other aspects of mitosis, cytokinesis, or chromosome replication. Thus, fibroblasts lacking Separase become highly polyploid. Hepatocytes stimulated to proliferate in vivo by hepatectomy also become unusually large and polyploid in the absence of Separase but are able to regenerate functional livers. Separase depletion in bone marrow causes aplasia and the presumed death of hematopoietic cells other than erythrocytes. Destruction of sister chromatid cohesion by Separase may be a universal feature of mitosis in eukaryotic cells

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia

Cycle cellulaire et centrosome (rôle de la protéine du transport intraflagellaire, Polaris, dans la transition G1/S)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Contrôle de la prolifération et de la polyploïdisation hépatique (rôles de l'insuline et de l'AMP-activated protein kinase)

Lors du développement post-natal du foie, ce tissu subit une polyploïdisation progressive qui débute au sevrage et aboutit à l émergence d hépatocytes tétraploïdes 4n et octoploïdes 8n, composés d un ou de deux noyaux (2x2n, 2x4n). Notre équipe a mis en évidence qu alors qu avant le sevrage tous les hépatocytes réalisent une cytodiérèse complète, après ce dernier, on observe des événements de cytodiérèse incomplète qui génèrent des hépatocytes binucléés. Durant ma thèse, nous avons démontré qu au sevrage, seules les modifications du signal insulinique jouent un rôle dans la mise en place de la polyploïdisation hépatocytaire. Nous démontrons que l inhibition de la voie PI3K/Akt (contrôlée par l insuline) se traduit par une diminution des événements de cytodiérèse incomplète dans les hépatocytes. Ces travaux représentent la 1ère démonstration que l insuline intervient dans le contrôle de la prolifération cellulaire en régulant les étapes tardives de la mitose. Récemment, les effets de l AMPK sur la polarité, la croissance et le contrôle de la ploïdie cellulaire ont été démontrés. Dans le foie, nous démontrons que la modulation de l activité AMPK n a pas d effet sur la mise en place de la ploïdie, mais qu elle entraîne une altération de la progression dans le cycle cellulaire. Des approches in vivo (Régénération Hépatique) et in vitro (Culture Primaire) révèlent que l absence d AMPK activée dans les hépatocytes en prolifération, entraîne un retard d entrée en phase S ainsi qu une inhibition de l expression de la cycline A. Nous démontrons un nouveau rôle de l AMPKa1 dans le contrôle de la prolifération hépatocytaire et ceci indépendamment du statut énergétique de la cellulePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Inhibiting Cytokinesis in the Liver: A New Way to Reduce Tumor Development

International audienc

Liver polyploidy: Dr Jekyll or Mr Hide?

International audienceno abstract