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Spatial heterogeneity in the mammalian liver


Hepatocytes operate in highly structured repeating anatomical units termed liver lobules. Blood flow along the lobule radial axis creates gradients of oxygen, nutrients and hormones, which, together with morphogenetic fields, give rise to a highly variable microenvironment. In line with this spatial variability, key liver functions are expressed non-uniformly across the lobules, a phenomenon termed zonation. Technologies based on single-cell transcriptomics have constructed a global spatial map of hepatocyte gene expression in mice revealing that ~50% of hepatocyte genes are expressed in a zonated manner. This broad spatial heterogeneity suggests that hepatocytes in different lobule zones might have not only different gene expression profiles but also distinct epigenetic features, regenerative capacities, susceptibilities to damage and other functional aspects. Here, we present genomic approaches for studying liver zonation, describe the principles of liver zonation and discuss the intrinsic and extrinsic factors that dictate zonation patterns. We also explore the challenges and solutions for obtaining zonation maps of liver non-parenchymal cells. These approaches facilitate global characterization of liver function with high spatial resolution along physiological and pathological timescales.

Key points

  • Hepatocytes residing along the lobule porto-central axis are exposed to different microenvironments, resulting in spatial zonation of liver tasks.

  • Single-cell technologies have enabled the reconstruction of zonation patterns for the global hepatocyte transcriptome, revealing principles of liver tissue organization.

  • Examples of optimal features of hepatocyte zonation include the assignment of energetically demanding tasks to highly oxygenated zones, spatial recycling of material and production line patterns.

  • Sequencing pairs of hepatocytes and adjacent non-parenchymal cells enables reconstruction of global zonation patterns of other liver cell types.

  • Liver zonation can give rise to zonated patterns of liver pathologies.

  • Zonation of gene expression is a prominent feature in other metabolic organs such as the intestine and the kidney.

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Fig. 1: Division of labour in the liver lobule.
Fig. 2: Zonation profiles of landmark genes using single-molecule fluorescence in situ hybridization.
Fig. 3: Single-cell spatial reconstruction of hepatocyte transcriptomes using landmark genes.
Fig. 4: Principles of hepatocyte zonation.
Fig. 5: Paired-cell RNA sequencing to infer liver endothelial cell zonation.
Fig. 6: Spatial heterogeneity in other metabolic tissues.


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The authors thank K. Bahar Halpern, Y. Shapira and A. Afriat for valuable comments. S.I. is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the Leir Charitable Foundations, the Richard Jakubskind Laboratory of Systems Biology, the Cymerman-Jakubskind Prize, the Lord Sieff of Brimpton Memorial Fund, the I-CORE programme of the Planning and Budgeting Committee and the Israel Science Foundation (grants 1902/ 12 and 1796/12), Israel Science Foundation grant number 1486/16, the European Molecular Biology Organization (EMBO) Young Investigator Program, the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013 and ERC grant agreement number 335122), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 768956), the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award.

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Nature Reviews Gastroenterology & Hepatology thanks S. Colnot, R. Gebhart and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Both authors contributed equally to this Review.

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Correspondence to Shalev Itzkovitz.

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Ben-Moshe, S., Itzkovitz, S. Spatial heterogeneity in the mammalian liver. Nat Rev Gastroenterol Hepatol 16, 395–410 (2019).

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