CELLULAR PLOIDY AND LIVER PHYSIOPATHOLOGY – LIVEPLOIDY
Polyploidy is a state in which cells possess more than two sets of homologous chromosomes (e.g. 4n, 8n). In physiological conditions, the conversion from diploidy to polyploidy is a part of development and differentiation programs. In certain tissues, the genesis of polyploid cells is also linked to a variety of cellular stressors (e.g. mechanical, genotoxic or metabolic stress). Alarmingly, proliferating polyploid cells are genetically unstable and thus mechanisms have evolved to limit their proliferation: activation of programmed death or senescence pathways; elicit immune responses resulting in their elimination. The liver is a polyploid organ. Up to 50% of human hepatocytes and 90% of mouse hepatocytes are polyploid; the vast majority being tetraploid with two nuclei (binuclear 2x2n). Partner 1 previously demonstrated that, during postnatal growth, hepatocytes accomplish adequate karyokinesis but fail to complete cytokinesis (genesis of binuclear cells). Partner 1 evidenced that during liver development, insulin (through PI3K/Akt pathway) is one of the major actor regulating polyploidization process. Importantly, throughout life, the liver is constantly exposed to various stressors. Beyond these injuries, hepatocytes retain the unique property to self-renew and to restore the liver ad integrum while preserving its ploidy/DNA integrity. Nevertheless, how polyploid hepatocytes behave in damaged livers, and influence disease progression are still unanswered questions. Recently, Partners 1 and 2 rationalized that liver diseases associated with insulin resistance could have an abnormal ploidy profile. Importantly, insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and plays a key role in the pathogenesis of type 2 diabetes (T2D) and the metabolic syndrome. Interestingly, using murine NAFLD models and cohort of patients, Partners 1 and 2 demonstrated the conversion of a physiological polyploidy (binuclear, DNA integrity) towards a pathological polyploidy (mononuclear =8n, DNA instability). Of note, this polyploid contingent is generated under a "DNA damage signal" (ATR/p53/p21) that precludes the activation of mitotic kinase. Importantly, oxidative stress was evidenced as a key player since antioxidant treatment was sufficient to restore a normal polyploid status.
In conclusion, the liver is the only organ that modulates its ploidy content both during its life span and following different types of stress. However, whether these polyploid hepatocytes have beneficial or detrimental effects on liver function, are still unanswered questions.
In that context, the aim of the proposal is dedicated to unveil how pathological polyploid cells behave in a damaged liver and what could be their relevance during disease progression. To achieve these objectives, we have brought together the scientific and technical expertises of three recognized teams in their respective field namely liver cell growth and ploidy DNA integrity (Partner 1), physiopathology of human liver diseases (Partner 2), DNA repair and immune response (Partner 3). Four major aims will then be developed:
(1) Unravel the mechanisms linking oxidative stress to pathological polyploid hepatocytes and their outcome in terms of proliferation and DNA integrity.
(2) Determine how polyploid hepatocytes is controlled by the immune system.
(3) Define whether polyploid hepatocytes within fatty liver parenchyma retain specific metabolic features.
(4) Define if a polyploid profile can be used as a prognostic marker of NAFLD/NASH sequence.
Madame Chantal DESDOUETS (INSTITUT NATIONALE DE LA SANTE ET DE LA RECHERCHE MEDICALE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Institut National de la Santé et de la Recherche Médicale
INSERM INSTITUT NATIONALE DE LA SANTE ET DE LA RECHERCHE MEDICALE
CRI - PARADIS Centre de Recherche sur l'Inflammation - Equipe PARADIS
Help of the ANR 494,972 euros
Beginning and duration of the scientific project: October 2016 - 36 Months