Semin Liver Dis 2023; 43(04): 460-471
DOI: 10.1055/a-2211-2144
Review Article

The Ploidy State as a Determinant of Hepatocyte Proliferation

1   Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
,
1   Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
› Institutsangaben
Funding This work was supported by grants to A.W.D. from the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases; U.S. Department of Health and Human Services) (R01 DK103645) and the Commonwealth of Pennsylvania. S.R.W. was supported by the National Institute of Biomedical Imaging and Bioengineering. NIBIB training grant, T32 EB001026, entitled “Cellular Approaches to Tissue Engineering and Regeneration.”


Abstract

The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the “ploidy conveyor,” undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.



Publikationsverlauf

Accepted Manuscript online:
15. November 2023

Artikel online veröffentlicht:
15. Dezember 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Patterson M, Swift SK. Residual diploidy in polyploid tissues: a cellular state with enhanced proliferative capacity for tissue regeneration?. Stem Cells Dev 2019; 28 (23) 1527-1539
  • 2 Orr-Weaver TL. When bigger is better: the role of polyploidy in organogenesis. Trends Genet 2015; 31 (06) 307-315
  • 3 Neiman M, Beaton MJ, Hessen DO, Jeyasingh PD, Weider LJ. Endopolyploidy as a potential driver of animal ecology and evolution. Biol Rev Camb Philos Soc 2017; 92 (01) 234-247
  • 4 Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nat Rev Cancer 2021; 21 (02) 89-103
  • 5 Weaver BA, Cleveland DW. Does aneuploidy cause cancer?. Curr Opin Cell Biol 2006; 18 (06) 658-667
  • 6 Sheltzer JM, Amon A. The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends Genet 2011; 27 (11) 446-453
  • 7 Segal DJ, McCoy EE. Studies on Down's syndrome in tissue culture. I. Growth rates and protein contents of fibroblast cultures. J Cell Physiol 1974; 83 (01) 85-90
  • 8 Milne LS. The histology of liver tissue regeneration. J Pathol Bacteriol 1909; 13 (01) 127-160
  • 9 Duncan AW, Taylor MH, Hickey RD. et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 2010; 467 (7316): 707-710
  • 10 Bou-Nader M, Caruso S, Donne R. et al. Polyploidy spectrum: a new marker in HCC classification. Gut 2020; 69 (02) 355-364
  • 11 Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A 2014; 111 (37) 13409-13414
  • 12 Duncan AW, Hanlon Newell AE, Bi W. et al. Aneuploidy as a mechanism for stress-induced liver adaptation. J Clin Invest 2012; 122 (09) 3307-3315
  • 13 Wilkinson PD, Alencastro F, Delgado ER. et al. Polyploid hepatocytes facilitate adaptation and regeneration to chronic liver injury. Am J Pathol 2019; 189 (06) 1241-1255
  • 14 Sladky VC, Eichin F, Reiberger T, Villunger A. Polyploidy control in hepatic health and disease. J Hepatol 2021; 75 (05) 1177-1191
  • 15 Donne R, Saroul-Aïnama M, Cordier P, Celton-Morizur S, Desdouets C. Polyploidy in liver development, homeostasis and disease. Nat Rev Gastroenterol Hepatol 2020; 17 (07) 391-405
  • 16 Gentric G, Desdouets C. Polyploidization in liver tissue. Am J Pathol 2014; 184 (02) 322-331
  • 17 Duncan AW. Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol 2013; 24 (04) 347-356
  • 18 Guidotti JE, Brégerie O, Robert A, Debey P, Brechot C, Desdouets C. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J Biol Chem 2003; 278 (21) 19095-19101
  • 19 Margall-Ducos G, Celton-Morizur S, Couton D, Brégerie O, Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci 2007; 120 (Pt 20): 3633-3639
  • 20 Matsumoto T, Wakefield L, Tarlow BD, Grompe M. In vivo lineage tracing of polyploid hepatocytes reveals extensive proliferation during liver regeneration. Cell Stem Cell 2020; 26 (01) 34-47.e3
  • 21 Wilkinson PD, Duncan AW. Differential roles for diploid and polyploid hepatocytes in acute and chronic liver injury. Semin Liver Dis 2021; 41 (01) 42-49
  • 22 Celton-Morizur S, Merlen G, Couton D, Desdouets C. Polyploidy and liver proliferation: central role of insulin signaling. Cell Cycle 2010; 9 (03) 460-466
  • 23 Celton-Morizur S, Merlen G, Couton D, Margall-Ducos G, Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest 2009; 119 (07) 1880-1887
  • 24 Pandit SK, Westendorp B, Nantasanti S. et al. E2F8 is essential for polyploidization in mammalian cells. Nat Cell Biol 2012; 14 (11) 1181-1191
  • 25 Chen HZ, Ouseph MM, Li J. et al. Canonical and atypical E2Fs regulate the mammalian endocycle. Nat Cell Biol 2012; 14 (11) 1192-1202
  • 26 Wilkinson PD, Delgado ER, Alencastro F. et al. The polyploid state restricts hepatocyte proliferation and liver regeneration in mice. Hepatology 2019; 69 (03) 1242-1258
  • 27 Kent LN, Rakijas JB, Pandit SK. et al. E2f8 mediates tumor suppression in postnatal liver development. J Clin Invest 2016; 126 (08) 2955-2969
  • 28 Hsu SH, Ghoshal K. MicroRNAs in liver health and disease. Curr Pathobiol Rep 2013; 1 (01) 53-62
  • 29 Hsu SH, Delgado ER, Otero PA. et al. MicroRNA-122 regulates polyploidization in the murine liver. Hepatology 2016; 64 (02) 599-615
  • 30 Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 2004; 304 (5672): 843-846
  • 31 Fava LL, Schuler F, Sladky V. et al. The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev 2017; 31 (01) 34-45
  • 32 Sladky VC, Knapp K, Szabo TG. et al. PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis. EMBO Rep 2020; 21 (12) e50893
  • 33 Liang CQ, Zhou DC, Peng WT. et al. FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes. NPJ Regen Med 2022; 7 (01) 33
  • 34 Diril MK, Ratnacaram CK, Padmakumar VC. et al. Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration. Proc Natl Acad Sci U S A 2012; 109 (10) 3826-3831
  • 35 Gentric G, Maillet V, Paradis V. et al. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 2015; 125 (03) 981-992
  • 36 Sladky VC, Knapp K, Soratroi C. et al. E2F-family members engage the PIDDosome to limit hepatocyte ploidy in liver development and regeneration. Dev Cell 2020; 52 (03) 335-349.e7
  • 37 Hsu SH, Duncan AW. Pathological polyploidy in liver disease. Hepatology 2015; 62 (03) 968-970
  • 38 Colnot S, Perret C. Molecular pathology of liver diseases. Liver zonation Springer US 2011; 5: 7-16
  • 39 Hoehme S, Brulport M, Bauer A. et al. Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A 2010; 107 (23) 10371-10376
  • 40 Soto-Gutierrez A, Gough A, Vernetti LA, Taylor DL, Monga SP. Pre-clinical and clinical investigations of metabolic zonation in liver diseases: the potential of microphysiology systems. Exp Biol Med (Maywood) 2017; 242 (16) 1605-1616
  • 41 Hijmans BS, Grefhorst A, Oosterveer MH, Groen AK. Zonation of glucose and fatty acid metabolism in the liver: mechanism and metabolic consequences. Biochimie 2014; 96: 121-129
  • 42 Wei Y, Wang YG, Jia Y. et al. Liver homeostasis is maintained by midlobular zone 2 hepatocytes. Science 2021; 371 (6532): eabb1625
  • 43 Paris J, Henderson NC. Liver zonation, revisited. Hepatology 2022; 76 (04) 1219-1230
  • 44 Jungermann K, Kietzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 1996; 16: 179-203
  • 45 Tanami S, Ben-Moshe S, Elkayam A, Mayo A, Bahar Halpern K, Itzkovitz S. Dynamic zonation of liver polyploidy. Cell Tissue Res 2017; 368 (02) 405-410
  • 46 Katsuda T, Hosaka K, Matsuzaki J. et al. Transcriptomic dissection of hepatocyte heterogeneity: linking ploidy, zonation, and stem/progenitor cell characteristics. Cell Mol Gastroenterol Hepatol 2020; 9 (01) 161-183
  • 47 Duncan AW. Single-cell and bulk transcriptome profiling reveals unique features of diploid and polyploid hepatocytes. Cell Mol Gastroenterol Hepatol 2020; 9 (01) 193-194
  • 48 Richter ML, Deligiannis IK, Yin K. et al. Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy. Nat Commun 2021; 12 (01) 4264
  • 49 Yang L, Wang X, Zheng JX. et al. Determination of key events in mouse hepatocyte maturation at the single-cell level. Dev Cell 2023; 58 (19) 1996-2010.e6
  • 50 Song Q, Ando A, Jiang N, Ikeda Y, Chen ZJ. Single-cell RNA-seq analysis reveals ploidy-dependent and cell-specific transcriptome changes in Arabidopsis female gametophytes. Genome Biol 2020; 21 (01) 178
  • 51 Jacobson EC, Pandya-Jones A, Plath K. A lifelong duty: how Xist maintains the inactive X chromosome. Curr Opin Genet Dev 2022; 75: 101927
  • 52 Balaton BP, Dixon-McDougall T, Peeters SB, Brown CJ. The eXceptional nature of the X chromosome. Hum Mol Genet 2018; 27 (R2): R242-R249
  • 53 Lu P, Prost S, Caldwell H, Tugwood JD, Betton GR, Harrison DJ. Microarray analysis of gene expression of mouse hepatocytes of different ploidy. Mamm Genome 2007; 18 (09) 617-626
  • 54 Lin YH, Zhang S, Zhu M. et al. Mice with increased numbers of polyploid hepatocytes maintain regenerative capacity but develop fewer hepatocellular carcinomas following chronic liver injury. Gastroenterology 2020; 158 (06) 1698-1712.e14
  • 55 Matsumoto T, Wakefield L, Grompe M. The significance of polyploid hepatocytes during aging process. Cell Mol Gastroenterol Hepatol 2021; 11 (05) 1347-1349
  • 56 Gaub J, Iversen J. Rat liver regeneration after 90% partial hepatectomy. Hepatology 1984; 4 (05) 902-904
  • 57 Gupta S. Hepatic polyploidy and liver growth control. Semin Cancer Biol 2000; 10 (03) 161-171
  • 58 Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 2003; 120 (01) 117-130
  • 59 Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miyajima A. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr Biol 2012; 22 (13) 1166-1175
  • 60 Overturf K, Al-Dhalimy M, Finegold M, Grompe M. The repopulation potential of hepatocyte populations differing in size and prior mitotic expansion. Am J Pathol 1999; 155 (06) 2135-2143
  • 61 Weglarz TC, Degen JL, Sandgren EP. Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am J Pathol 2000; 157 (06) 1963-1974
  • 62 Heinke P, Rost F, Rode J. et al. Diploid hepatocytes drive physiological liver renewal in adult humans. Cell Syst 2022; 13 (06) 499-507.e12
  • 63 Viswanathan P, Sharma Y, Gupta P, Gupta S. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration. Cell Prolif 2018; 51 (03) e12445
  • 64 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66 (01) 7-30
  • 65 Sato N, Mizumoto K, Nakamura M. et al. Centrosome abnormalities in pancreatic ductal carcinoma. Clin Cancer Res 1999; 5 (05) 963-970
  • 66 Olaharski AJ, Sotelo R, Solorza-Luna G. et al. Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis 2006; 27 (02) 337-343
  • 67 Lothschütz D, Jennewein M, Pahl S. et al. Polyploidization and centrosome hyperamplification in inflammatory bronchi. Inflamm Res 2002; 51 (08) 416-422
  • 68 Saeter G, Schwarze PE, Nesland JM, Juul N, Pettersen EO, Seglen PO. The polyploidizing growth pattern of normal rat liver is replaced by divisional, diploid growth in hepatocellular nodules and carcinomas. Carcinogenesis 1988; 9 (06) 939-945
  • 69 Schwarze PE, Saeter G, Armstrong D. et al. Diploid growth pattern of hepatocellular tumours induced by various carcinogenic treatments. Carcinogenesis 1991; 12 (02) 325-327
  • 70 Nagasue N, Kohno H, Chang YC. et al. DNA ploidy pattern in synchronous and metachronous hepatocellular carcinomas. J Hepatol 1992; 16 (1–2): 208-214
  • 71 Zhang S, Zhou K, Luo X. et al. The polyploid state plays a tumor-suppressive role in the liver. Dev Cell 2018; 44 (04) 447-459.e5
  • 72 Matsuura T, Ueda Y, Harada Y. et al. Histological diagnosis of polyploidy discriminates an aggressive subset of hepatocellular carcinomas with poor prognosis. Br J Cancer 2023; 129 (08) 1251-1260
  • 73 Lin H, Huang YS, Fustin JM. et al. Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver. Nat Commun 2021; 12 (01) 645
  • 74 Matsumoto T. Implications of polyploidy and ploidy alterations in hepatocytes in liver injuries and cancers. Int J Mol Sci 2022; 23 (16) 9409
  • 75 Matsumoto T, Wakefield L, Peters A, Peto M, Spellman P, Grompe M. Proliferative polyploid cells give rise to tumors via ploidy reduction. Nat Commun 2021; 12 (01) 646