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Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
Open accessAbstract
The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity.
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“recent studies have demonstrated that hepatocytes are primarily maintained by the proliferation of pre-existing hepatocytes during liver homeostasis and regeneration14–19”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In the mouse and human liver, Wnt ligands are produced by endothelial cells of the central vein branches and the nearby sinusoids (17–19)”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [17]
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“In the mouse and human liver, Wnt ligands are produced by endothelial cells of the central vein branches and the nearby sinusoids (McEnerney et al. 2017;Wang et al. 2015;Zhao et al. 2019), creating a zonated expression pattern of Wnt target genes and key metabolic enzymes in pericentral hepatocytes (Halpern et al. 2017).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Wang et al. 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“The transcriptional repressor Tbx3, a gene required for embryonic liver development (Khan et al. 2020;Ludtke et al. 2009;Suzuki et al. 2008), is also expressed in a zonated pattern during postnatal liver growth (fig.S1A) (Wang et al. 2015;Zhao et al. 2019).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Wang et al. 2015
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“Among the genes highly expressed in the pericentral zone is the transcriptional repressor Tbx3 (17, 19).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [17]
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“Additionally, lineage-tracing data have shown that hepatocytes in the different zones can adopt the gene expression programme of the new zone they reside in.49,60,84,86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [49]
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Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities
Nusse, R., & Clevers, H. (2017) · Cell · doi:10.1016/j.cell.2017.05.016 · Cited by 4,342
Self-citationLiver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis
Sia, D., Villanueva, A., Friedman, S. L., & Llovet, J. M. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.11.048 · Cited by 1,181
A human liver cell atlas reveals heterogeneity and epithelial progenitors
Aizarani, N., Saviano, A., Sagar, Mailly, L., Durand, S., Herman, J. S., Pessaux, P., Baumert, T. F., & Grün, D. (2019) · Nature · doi:10.1038/s41586-019-1373-2 · Cited by 1,147
Single-cell spatial reconstruction reveals global division of labour in the mammalian liver
Halpern, K. B., Shenhav, R., Matcovitch-Natan, O., Tóth, B., Lemze, D., Golan, M., Massasa, E. E., Baydatch, S., Landen, S., Moor, A. E., et al. (2017) · Nature · doi:10.1038/nature21065 · Cited by 1,059
Liver regeneration: biological and pathological mechanisms and implications
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Metadata
- Authors
- Wang, B., Zhao, L., Fish, M., Logan, C. Y., & Nusse, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wang, Bruce
- Venue
- Nature
- Published
- 2015-08-05
- Volume
- 524
- Issue
- 7564
- Pages
- 180-185
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4589224
- OpenAlex
- W1628437161
- Cited by
- 674
- References
- 50
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 33 · 2023: 61 · 2022: 52 · 2021: 90 · 2020: 88 · 2019: 66 · 2018: 85 · 2017: 69 · 2016: 67 · 2015: 19
- FWCI
- 47.42
- Type
- journal article
- Language
- en
- 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)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK101603, F32DK091005, P30DK026743)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- liver homeostasis, Axin2, Wnt signaling, TBX3, liver progenitor cells, polyploidy, self-renewal, stem cell niche, lineage tracing
- MeSH terms
- Animals, Clone Cells, Diploidy, Female, Homeostasis, Liver, Male, Polyploidy, Regeneration, Staining and Labeling, Stem Cells, Time Factors, Veins, Biomarkers, Cell Lineage, T-Box Domain Proteins, Hepatocytes, Endothelial Cells, Cell Proliferation, Mice, Stem Cell Niche, Wnt Signaling Pathway, Axin Protein
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