Cell and Tissue Research

, Volume 368, Issue 2, pp 405–410 | Cite as

Dynamic zonation of liver polyploidy

  • Sivan Tanami
  • Shani Ben-Moshe
  • Anat Elkayam
  • Avi Mayo
  • Keren Bahar Halpern
  • Shalev Itzkovitz
Short Communication


The liver is a polyploid organ, consisting of hepatocytes with one or two nuclei each containing 2, 4, 8 or more haploid chromosome sets. The dynamic changes in the spatial distributions of polyploid classes across the liver lobule, its repeating anatomical unit, have not been characterized. Identifying these spatial patterns is important for understanding liver homeostatic and regenerative turnover, as well as potential division of labor among ploidy classes. Here, we use single molecule-based tissue imaging to reconstruct the spatial zonation profiles of liver polyploid classes in mice of different ages. We find that liver polyploidy proceeds in spatial waves, advancing more rapidly in the mid-lobule zone compared to the periportal and perivenous zones. We also measure the spatial zonation profiles of S-phase entry at different ages and identify more rapid S-phase entry in the mid-lobule zone at older ages. Our findings reveal fundamental features of liver spatial heterogeneity and highlight their dynamic changes during development and aging.


Liver zonation Liver polyploidy Systems biology Single molecule imaging Stem cells 



We thank Shanie Landen for valuable comments on the manuscript. S.I. is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, The Leir Charitable Foundations, Richard Jakubskind Laboratory of Systems Biology, Cymerman-Jakubskind Prize, The Lord Sieff of Brimpton Memorial Fund, The Human Frontiers Science Program, the I-CORE program of the Planning and Budgeting Committee and the Israel Science Foundation, the European Molecular Biology Organization Young Investigator Program and the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement number 335122. S.I. is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair.

Supplementary material

441_2016_2427_MOESM1_ESM.pdf (62 kb)
ESM 1 (PDF 61 kb)
441_2016_2427_MOESM2_ESM.pdf (53 kb)
ESM 2 (PDF 52 kb)


  1. Achim K, Pettit J-B, Saraiva LR et al (2015) High-throughput spatial mapping of single-cell RNA-seq data to tissue of origin. Nat Biotechnol 33:503–509. doi: 10.1038/nbt.3209 CrossRefPubMedGoogle Scholar
  2. Bahar Halpern K, Tanami S, Landen S et al (2015) Bursty Gene Expression in the Intact Mammalian Liver. Mol Cell 58:147–156. doi: 10.1016/j.molcel.2015.01.027 CrossRefPubMedGoogle Scholar
  3. Braeuning A, Ittrich C, Köhle C et al (2006) Differential gene expression in periportal and perivenous mouse hepatocytes. FEBS J 273:5051–5061. doi: 10.1111/j.1742-4658.2006.05503.x CrossRefPubMedGoogle Scholar
  4. Bralet MP, Branchereau S, Brechot C, Ferry N (1994) Cell lineage study in the liver using retroviral mediated gene transfer. Evidence against the streaming of hepatocytes in normal liver. Am J Pathol 144:896–905PubMedPubMedCentralGoogle Scholar
  5. Celton-Morizur S, Desdouets C (2010) Polyploidization of liver cells. Adv Exp Med Biol 676:123–135CrossRefPubMedGoogle Scholar
  6. Celton-Morizur S, Merlen G, Couton D et al (2009) The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest 119:1880–1887. doi: 10.1172/JCI38677 PubMedPubMedCentralGoogle Scholar
  7. Colnot S, Perret C (2011) Liver zonation. In: Monga SPS (ed) Molecular pathology of liver diseases. Springer, New York, pp 7–16Google Scholar
  8. Duncan AW (2013) Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol 24:347–356 doi: 10.1016/j.semcdb.2013.01.003 CrossRefPubMedGoogle Scholar
  9. Duncan AW, Taylor MH, Hickey RD et al (2010) The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467:707–710. doi: 10.1038/nature09414 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Epstein CJ (1967) Cell size, nuclear content, and the development of polyploidy in the mammalian liver. Proc Natl Acad Sci U S A 57:327–334CrossRefPubMedPubMedCentralGoogle Scholar
  11. Font-Burgada J, Shalapour S, Ramaswamy S et al (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell 162:766–779. doi: 10.1016/j.cell.2015.07.026 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gebhardt R (1992) Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther 53:275–354CrossRefPubMedGoogle Scholar
  13. Gentric G, Desdouets C (2014) Polyploidization in liver tissue. Am J Pathol 184:322–331. doi: 10.1016/j.ajpath.2013.06.035 CrossRefPubMedGoogle Scholar
  14. Gujral JS, Knight TR, Farhood A et al (2002) Mode of Cell Death after Acetaminophen Overdose in Mice: Apoptosis or Oncotic Necrosis? Toxicol Sci 67:322–328. doi: 10.1093/toxsci/67.2.322 CrossRefPubMedGoogle Scholar
  15. Jones BA, Gores GJ (1997) Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine. Am J Physiol 273:G1174–1188PubMedGoogle Scholar
  16. Jungermann K, Keitzmann T (1996) Zonation of Parenchymal and Nonparenchymal Metabolism in Liver. Annu Rev Nutr 16:179–203. doi: 10.1146/ CrossRefPubMedGoogle Scholar
  17. Kanzler S, Galle PR (2000) Apoptosis and the liver. Semin Cancer Biol 10:173–184. doi: 10.1006/scbi.2000.0318 CrossRefPubMedGoogle Scholar
  18. Lu P, Prost S, Caldwell H et al (2007) Microarray analysis of gene expression of mouse hepatocytes of different ploidy. Mamm Genome 18:617–626. doi: 10.1007/s00335-007-9048-y CrossRefPubMedGoogle Scholar
  19. Margall-Ducos G, Celton-Morizur S, Couton D et al (2007) Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci 120:3633–3639. doi: 10.1242/jcs.016907 CrossRefPubMedGoogle Scholar
  20. Martin NC, McCullough CT, Bush PG et al (2002) Functional analysis of mouse hepatocytes differing in DNA content: volume, receptor expression, and effect of IFNgamma. J Cell Physiol 191:138–144. doi: 10.1002/jcp.10057 CrossRefPubMedGoogle Scholar
  21. Morales-Navarrete H, Segovia-Miranda F, Klukowski P et al (2015) A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture. eLife 4, e11214. doi: 10.7554/eLife.11214 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Pandit SK, Westendorp B, Nantasanti S et al (2012) E2F8 is essential for polyploidization in mammalian cells. Nat Cell Biol 14:1181–1191. doi: 10.1038/ncb2585 CrossRefPubMedGoogle Scholar
  23. Satija R, Farrell JA, Gennert D et al (2015) Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33:495–502. doi: 10.1038/nbt.3192 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Schmucker DL (2005) Age-related changes in liver structure and function: Implications for disease ? Exp Gerontol 40:650–659. doi: 10.1016/j.exger.2005.06.009 CrossRefPubMedGoogle Scholar
  25. Wang M-J, Chen F, Li J-X et al (2014) Reversal of hepatocyte senescence after continuous in vivo cell proliferation. Hepatol Baltim Md 60:349–361. doi: 10.1002/hep.27094 CrossRefGoogle Scholar
  26. Wang B, Zhao L, Fish M et al (2015) Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. Nature 524:180–185. doi: 10.1038/nature14863 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Sivan Tanami
    • 1
  • Shani Ben-Moshe
    • 1
  • Anat Elkayam
    • 1
  • Avi Mayo
    • 1
  • Keren Bahar Halpern
    • 1
  • Shalev Itzkovitz
    • 1
  1. 1.Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael

Personalised recommendations