The impact of liver polyploidization on Non

ED BIO SORBONNE PARIS CITE
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : INSTITUT COCHIN INSERM U1016 UMR CNRS8104 UNIVERSITE PARIS
DESCARTES
Nom et prénom du Directeur : DR PIERRE-OLIVIER COURAUD
Téléphone :
01 40 51 64 57
Télécopie : 01 40 51 64 73
courriel : [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Cycle cellulaire et physiopathologie du foie
Nom et prénom du responsable : Dr. Chantal DESDOUETS
Qualité du responsable : DR2 INSERM
Téléphone :
01 44 41 24 39
Télécopie : 01 44 41 24 21
courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Chantal DESDOUETS
Qualité : DR2 INSERM
Téléphone :
01 44 41 24 39
Télécopie : 01 44 41 24 21
courriel : [email protected]
Titre du sujet proposé :
(en français) Impact de la ploïdie dans les maladies non alcooliques du foie
(en anglais) The impact of liver polyploidization on Non-Alcoholic Fatty Liver Diseases (NAFLD)
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :




Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary:
The liver performs multiple functions to ensure maintenance of homeostasis. The hepatocyte is the most
abundant cell of the liver. In adults, hepatocytes are quiescent and highly differentiated cells.
Distinctively, hepatocytes are polyploids. Throughout life, hepatocytes are constantly exposed to
different stressors. Beyond these injuries, hepatocytes retain the unique property to self-renew and to
repair the liver ad integrum. In this context, our team is committed to decipher how ploidy, metabolicgenotoxic stress and inflammatory response impact on hepatocytes division integrity during pathological
settings.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Nom, prénom du directeur de l'unité de recherche : Dr. Pierre-Olivier COURAUD
Numéro de l'unité de recherche (et établissement de rattachement) : Institut Cochin INSERM u1016,
UMR CNRS8104, Université Paris Descartes
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Dr. Chantal DESDOUETS, DR2 INSERM
Nom, prénom du directeur de thèse : Dr. Chantal DESDOUETS, DR2 INSERM
Titre du sujet de thèse proposé : Impact de la ploïdie dans les maladies non alcooliques du foie
(en anglais) The impact of liver polyploidization on Non-Alcoholic Fatty Liver Diseases (NAFLD)
Citer 5 mots clés : Foie, Hépatocytes, Stéatose, Ploïdie, Cycle Cellulaire
(key words) : Liver, Hepatocytes, Steatosis, Ploidy, Cell Cycle
Candidat pressenti :

OUI

NON
Contenu scientifique du programme de la thèse (en anglais)
The liver is a physiological polyploid organ. In adult human, up to 50% of hepatocytes are polyploid; the
vast majority being tetraploid with two nuclei (binuclear 2x2n). We previously demonstrated that, during
postnatal growth, hepatocytes accomplish adequate karyokinesis but fail to complete cytokinesis
(genesis of binuclear cells). We also evidenced that during liver development, insulin (through PI3K/Akt
pathway) is one of the major actor regulating polyploidization process. Recently, we rationalized that liver
diseases associated with insulin resistance could have an abnormal ploidy profile. Importantly, insulin
resistance plays a key role in the pathogenesis of type 2 diabetes (T2D) and obesity. These pathologies
are now considered as a social and economic burden. The liver is a central organ affected by these
conditions resulting in a high level of fat accumulation, defined as NAFLD (Non Alcoholic Fatty Liver
Disease). Alarmingly NAFLD progresses pejoratively to NASH (Non Alcoholic Steato- Hepatitis) and
evolve in some cases to hepatocellular carcinoma (HCC). The prevalence of NAFLD is currently
estimated to range 5-20% in the general population. Therefore, increasing knowledge on the metabolic
disorders is thus a major public health issue. Interestingly, using murine NAFLD models and cohort of
patients, we demonstrated the conversion of a physiological polyploidy (tetraploid binuclear, DNA
integrity) into a pathological polyploidy (polyploid mononuclear 4n, ≥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 (endoreplication cycle). Importantly, oxidative stress was evidenced as a key
player. Collectively, these new findings, demonstrate for the first time within damaged liver, the genesis
of pathological polyploid hepatocytes exhibiting a strong potential of genomic instability.
The main goal of the PhD project is to determine how pathological polyploid cells behave in damaged
liver and their relevance during disease progression. The project is divided into different axes: (1)
Determination of the mechanisms linking oxidative/DNA replication stress to pathological polyploidy. (2)
Define the outcome of polyploid fraction in terms of proliferation, DNA integrity (3) Determine if a
polyploid profile can be used as a pronostic marker of NAFLD/NASH sequence. To reach the goals, the
experimental strategy is mainly based on the use of animal models associated with central technologies
as hepatocytes primary culture, specific ploidy cell sorting, omics analyses and dedicated quantitative
ploidy imaging system. Translational research will be performed in collaboration with clinical teams.
Indiquez les trois meilleures publications récentes sur le sujet :
Gentric G, Maillet V, Paradis V, Couton D, L'Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S,
Desdouets C. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J
Clin Invest, 2015,125, 981-992.
Merlen G., Gentric G., Celton-Morizur S., Foretz M., Guidotti JE., Fauveau V., Leclerc J., Viollet
B., Desdouets C. AMPKα1 controls hepatocyte proliferation independently of energy balance by
regulating Cyclin A2 expression. Journal of Hepatology, 2014, Jan; 60(1):152-9.
Espeillac, C., Mitchell, C., Celton-Morizur, S., Chauvin, C., Koka, V., Gillet, C., Albrecht, J. H.,
Desdouets, C., and Pende, M. S6 kinase 1 is required for rapamycin-sensitive liver proliferation after
mouse hepatectomy. J Clin Invest, 2011,121, 2821-2832.