Single-cell spatial reconstruction reveals global division of labour in the mammalian liver
Open accessAbstract
The mammalian liver consists of hexagon-shaped lobules that are radially polarized by blood flow and morphogens. Key liver genes have been shown to be differentially expressed along the lobule axis, a phenomenon termed zonation, but a detailed genome-wide reconstruction of this spatial division of labour has not been achieved. Here we measure the entire transcriptome of thousands of mouse liver cells and infer their lobule coordinates on the basis of a panel of zonated landmark genes, characterized with single-molecule fluorescence in situ hybridization. Using this approach, we obtain the zonation profiles of all liver genes with high spatial resolution. We find that around 50% of liver genes are significantly zonated and uncover abundant non-monotonic profiles that peak at the mid-lobule layers. These include a spatial order of bile acid biosynthesis enzymes that matches their position in the enzymatic cascade. Our approach can facilitate the reconstruction of similar spatial genomic blueprints for other mammalian organs.
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Hepatocytes are the major parenchymal component of the liver, accounting for approximately 80% of its mass.
“Hepatocytes, the major parenchymal (epithelial) component of the liver accounting for approximately 80% of its mass”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [10]
The main text (page unavailable) describes liver lobules as composed of layers of hepatocytes, supporting their central role in liver tissue. It does not state that hepatocytes account for approximately 80% of liver mass; a search for “80%” found no such figure. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese three hepatocyte zones are in agreement with earlier spatial transcriptomics studies.
“These zones are in agreement with earlier spatial transcriptomics studies6,8.”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [6]
The main text and Extended Data Figure 7 report that the paper’s periportal and pericentral expression patterns agree with previous studies. But the paper reconstructs a gradient across nine lobule layers and identifies additional patterns in intermediate layers; it does not establish agreement on three discrete hepatocyte zones. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese observations are consistent with the classic zonation described in human and mouse liver, supporting the MERFISH measurements.
“Collectively, these observations are consistent with the classic zonation described in human and mouse liver4,24–26, supporting our MERFISH measurements.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [26]
The main text describes established liver zonation and reports zonation profiles in mouse liver; it also says those profiles correlated with earlier datasets. This supports the mouse-liver portion of the cited background, but the paper does not establish zonation in human liver. The statement that this supports the citing authors’ MERFISH measurements is their own inference. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn healthy human liver, hepatocyte zonation reflects a continuous gradient from periportal to pericentral regions rather than distinct zones.
“While MERFISH allows to us to define these zones, it is also evident through pseudotime analysis, measurement of gene expression across individual lobules, and transcriptional analysis performed across lobules, that zonation reflects a gradient from periportal to pericentral regions rather than distinct zones.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [26]
The main text reports clear hepatocyte expression gradients and says the findings challenge a binary periportal–pericentral classification. However, it specifies that the zonation profiles studied were from fasted mice, not healthy human liver. The paper therefore supports the gradient interpretation but not the claimed human population. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWnt target genes and key metabolic enzymes have a zonated expression pattern in pericentral hepatocytes.
“creating a zonated expression pattern of Wnt target genes and key metabolic enzymes in pericentral hepatocytes (20–22).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [21]
Previous single-cell and spatial transcriptomics studies have shown that the hepatocyte transcriptome varies along the portocentral axis.
“Previous single-cell and spatial transcriptomics studies have shown that not only hepatocyte function, but also their transcriptome, varies along this axis6.”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [6]
Spatial gene expression in human hepatocytes is better described by a continuous variable determined by the relative distance between the portal and central areas of the lobule, similar to observations in mouse.
“Collectively, these observations suggest that spatial gene expression in human hepatocytes is better described by a continuous variable determined by the relative distance between the portal and central areas of the lobule, similar to observations in mouse7,26,27.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [26]
Previous single-cell and spatial transcriptomics studies have shown that hepatocyte transcriptome varies along the porto-central axis.
“Previous single-cell and spatial transcriptomics studies have shown that not only hepatocyte function, but also transcriptome, varies along this axis8.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [8]
SDS was enriched in zone 1 (periportal), while CYP2E1 expression increased in zone 3 (pericentral), as previously described in mouse.
“SDS was enriched in zone 1 (periportal), while CYP2E1 expression increased in zone 3 (pericentral), as previously described in mouse24–27 (Fig. 1c, e, f; Supplementary Fig. 5a).”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [26]
The Extended Data Figure 9 caption reports a pericentral bias for liver detoxification genes, including cytochrome P450 genes, but does not identify CYP2E1. Searches for SDS and CYP2E1 found no passages in our copy stating either gene’s zonation, so the specific mouse findings attributed to this paper cannot be verified. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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- Authors
- Halpern, K. B., Shenhav, R., Matcovitch-Natan, O., Tóth, B., Lemze, D., Golan, M., Massasa, E. E., Baydatch, S., Landen, S., Moor, A. E., Brandis, A., Giladi, A., Stokar-Avihail, A., David, E., Amit, I., & Itzkovitz, S.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Amit, Ido
- Itzkovitz, Shalev
- ORCID
- Venue
- Nature
- Published
- 2017-02-06
- Volume
- 542
- Issue
- 7641
- Pages
- 352-356
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5321580
- OpenAlex
- W2585175142
- Cited by
- 1,059
- References
- 7
- Citations by year
- 2026: 112 · 2025: 129 · 2024: 99 · 2023: 127 · 2022: 132 · 2021: 135 · 2020: 130 · 2019: 92 · 2018: 73 · 2017: 27
- FWCI
- 36.09
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-03-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- liver zonation, spatial gene expression, single-cell spatial transcriptomics, single-molecule fluorescence in situ hybridization, mouse liver, lobules, bile acid synthesis, central vein
- MeSH terms
- Single Molecule Imaging, Animals, Bile Acids and Salts, Liver, Male, Mice, Inbred C57BL, Genome, In Situ Hybridization, Fluorescence, Sequence Analysis, RNA, Gene Expression Profiling, Hepatocytes, Mice, Single-Cell Analysis, Transcriptome
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