A human liver cell atlas reveals heterogeneity and epithelial progenitors
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Abstract
The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2 int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers.
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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 [11]
The Single-Cell RNA-seq of the human liver section identifies hepatocytes as a main liver cell type, and the Extended Data say they strongly dominate samples collected without enrichment. Neither passage states that hepatocytes account for approximately 80% of liver mass; the sampled-cell proportions cannot establish that figure. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRNA sequencing studies revealed evidence of differentiation, with early lineage genes being downregulated in favor of increased expression of genes associated with hepatic maturation, hematopoiesis, and stromal development, reaching levels intermediate between fetal and adult human liver, accompanied by an upregulation of genes related to regeneration.
“RNA sequencing studies revealed evidence of differentiation, with early lineage genes—which are predominant in fetal liver—being downregulated in favor of increased expression of genes associated with hepatic maturation, hematopoiesis, and stromal development, reaching levels intermediate between fetal and adult human liver, accompanied by an upregulation of genes related to regeneration [23,41,42”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [23]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredBoth macrophage populations were identified by expression of CD74, while Mac 2 cells also expressed CD5L and MARCO, most consistent with non-inflammatory macrophages or Kupffer cells.
“Both macrophage populations were identified by expression of CD74, while Mac 2 cells also expressed CD5L and MARCO (Fig. 2d, i; Supplementary Fig. 6b), most consistent with non-inflammatory macrophages or Kupffer cells10,11,21.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [21]
ALDOB expression was observed in sheets of cells consistent with hepatocytes.
“We observed sheets of cells expressing ALDOB, consistent with hepatocytes21 (Supplementary Fig. 2), while CD5L expression was clustered in spaces between hepatocytes consistent with resident macrophages located in sinusoids10 (Supplementary Fig. 2a–f).”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [21]
The Zonation of human liver cell types section identifies other hepatocyte-associated genes, including ALB and PCK1, but does not mention ALDOB. Searches of our copy for ALDOB, aldolase B, and hepatocyte sheets found no passage linking ALDOB expression to hepatocytes or describing the sheet-like pattern. (LLM, conf=0.70)
Experimental — accuracy not yet measuredMost B-cell subsets, such as mature, immature, B2, B1, and plasma cells, have been detected in the human liver.
“Although their precise function at steady state is less clear, most B‐cell subsets, such as mature, immature, B2, B1, and plasma cells, have been detected in the human liver.( 43 , 44 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [44]
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- Authors
- Aizarani, N., Saviano, A., Sagar, Mailly, L., Durand, S., Herman, J. S., Pessaux, P., Baumert, T. F., & Grün, D.
- Affiliations
- University of Freiburg (DE)
- Inserm (FR)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Corresponding author
- Baumert, Thomas F.
- Grün, Dominic
- ORCID
- Venue
- Nature
- Published
- 2019-07-10
- Volume
- 572
- Issue
- 7768
- Pages
- 199-204
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6687507
- OpenAlex
- W2959566316
- Cited by
- 1,147
- References
- 75
- Citations by year
- 2026: 125 · 2025: 152 · 2024: 162 · 2023: 158 · 2022: 165 · 2021: 206 · 2020: 154 · 2019: 24
- FWCI
- 46.23
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- univOAK (4 institutions : Université de Strasbourg, Université de Haute Alsace, INSA Strasbourg, Bibliothèque Nationale et Universitaire de Strasbourg) (submittedVersion, cc-by-sa)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- European Commission (ERC-AdG-2014-671231-HEPCIR, ERC-AdG-2014, EU-H2020, #671231, 667273, H2020, ERC-PoC-2016-PRELICAN, LABEX ANR-10-LABX-0028_HEPSYS)
- Deutsche Forschungsgemeinschaft (SPP193 7, GR4980/1-1, EXC‐2189, 390939984, GRK 2344, GR4980/3-1)
- Agence Nationale de la Recherche (ANR-10-IDEX-0002, ANR-10, ANR-10-LABX-0028)
- Institut National de la Santé et de la Recherche Médicale
- Université de Strasbourg
- Max-Planck-Gesellschaft
- Horizon 2020 Framework Programme (EU‐H2020, H2020-667273-HEPCAR, 667273)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- epithelial progenitors, cholangiocytes, Kupffer cells, liver endothelial cells, TROP2, hepatocellular carcinoma, liver zonation
- MeSH terms
- RNA-Seq, Adult, Animals, Antigens, Neoplasm, Chimera, Epithelial Cells, Female, Gene Expression Regulation, Carcinoma, Hepatocellular, Humans, Liver, Male, Organoids, Stem Cells, Reproducibility of Results, Cell Adhesion Molecules, RNA, Small Cytoplasmic, Hepatocytes, Endothelial Cells, Mice
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