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Polyploidy in liver development, homeostasis and disease

Abstract

Polyploidy (or whole-genome duplication) is the condition of having more than two basic sets of chromosomes. Polyploidization is well tolerated in many species and can lead to specific biological functions. In mammals, programmed polyploidization takes place during development in certain tissues, such as the heart and placenta, and is considered a feature of differentiation. However, unscheduled polyploidization can cause genomic instability and has been observed in pathological conditions, such as cancer. Polyploidy of the liver parenchyma was first described more than 100 years ago. The liver is one of the few mammalian organs that display changes in polyploidy during homeostasis, regeneration and in response to damage. In the human liver, approximately 30% of hepatocytes are polyploid. The polyploidy of hepatocytes results from both nuclear polyploidy (an increase in the amount of DNA per nucleus) and cellular polyploidy (an increase in the number of nuclei per cell). In this Review, we discuss the regulation of polyploidy in liver development and pathophysiology. We also provide an overview of current knowledge about the mechanisms of hepatocyte polyploidization, its biological importance and the fate of polyploid hepatocytes during liver tumorigenesis.

Key points

  • Polyploidy, a condition in which cells contain more than two sets of homologous chromosomes, is a well-known feature of mammalian hepatocytes.

  • Polyploidy is defined on the basis of the DNA content of each nucleus (nuclear ploidy; for example, 2n, 4n or 8n) and the number of nuclei per cell (cellular ploidy).

  • The adult liver contains a heterogeneous mixture of diploid and polyploid hepatocytes.

  • The liver is one of the few mammalian organs that display changes in ploidy during normal homeostasis, during regeneration and in response to damage.

  • The polyploid state could provide protection from tumorigenesis by providing extra copies of tumour suppressor genes.

  • Amplification of nuclear ploidy within liver tumours is associated with a poor prognosis.

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Fig. 1: Characteristics of polyploidy.
Fig. 2: Molecular mechanisms that lead to the polyploid state.
Fig. 3: Polyploidization during postnatal liver growth.
Fig. 4: Genesis of mononucleate polyploid hepatocytes in physiopathological contexts.
Fig. 5: The polyploid state: gatekeeper or driver of liver tumorigenesis?

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Acknowledgements

The authors are supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), la Fondation pour la Recherche Médicale (Equipe FRM: EQU201903007824), the Institut National du Cancer (PRTK-2017, PLBIO18-107), the Agence Nationale de Recherche ANR (ANR-16-CE14), Fondation ARC (Association de Recherche sur le Cancer), Ligue Contre le Cancer (comité de Paris), the Cancéropôle Ile-de-France (Emergence 2015), The Association Française pour l’Etude du Foie (AFEF-SUBV 2017), EVA-Plan Cancer INSERM HTE and the SIRIC CARPEM. R.D. is a recipient of Fondation pour la Recherche Médicale (PhD grant). P.C. is a recipient of Plan Cancer INSERM (program « Soutien pour la formation à la recherche fondamentale et translationnelle en cancérologie »).

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R.D., M.S.-A. and P.C. wrote the article and researched data for the article. S.C.-M. wrote the article and made a substantial contribution to the discussion of content. C.D. wrote the article, researched data for the article, made a substantial contribution to the discussion of content and reviewed/edited the manuscript before submission.

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Correspondence to Chantal Desdouets.

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Donne, R., Saroul-Aïnama, M., Cordier, P. et al. Polyploidy in liver development, homeostasis and disease. Nat Rev Gastroenterol Hepatol 17, 391–405 (2020). https://doi.org/10.1038/s41575-020-0284-x

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