The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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.
In the citing paper
“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]
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.
In the citing paper
“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.
In the citing paper
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288
Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., & Salzberg, S. L. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r36 · Cited by 12,668
Identification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687
Goecks, J., Nekrutenko, A., Taylor, J., & The Galaxy Team (2010) · Genome biology · doi:10.1186/gb-2010-11-8-r86 · Cited by 3,532
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
Differential analysis of gene regulation at transcript resolution with RNA-seq
Trapnell, C., Hendrickson, D. G., Sauvageau, M., Goff, L., Rinn, J. L., & Pachter, L. (2013) · Nature Biotechnology · doi:10.1038/nbt.2450 · Cited by 3,492
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491
(2012) · doi:10.1016/j.jmoldx.2011.08.002 · Cited by 2,567
The advantages and disadvantages of being polyploid
Comai, L. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1711 · Cited by 2,308
Defining the Epithelial Stem Cell Niche in Skin
Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E., Rendl, M., & Fuchs, E. (2004) · Science · doi:10.1126/science.1092436 · Cited by 2,031
In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
Huch, M., Dorrell, C., Boj, S. F., van Es, J. H., Li, V. S. W., van de Wetering, M., Sato, T., Hamer, K., Sasaki, N., Finegold, M. J., et al. (2013) · Nature · doi:10.1038/nature11826 · Cited by 1,555
An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control
Clevers, H. C., Loh, K. M., & Nusse, R. (2014) · Science · doi:10.1126/science.1248012 · Cited by 1,386
Self-citationLustig, B., Jerchow, B., Sachs, M., Weiler, S., Pietsch, T., Karsten, U., van de Wetering, M., Clevers, H., Schlag, P., Birchmeier, W., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.4.1184-1193.2002 · Cited by 1,198
The adult Drosophila posterior midgut is maintained by pluripotent stem cells
Ohlstein, B., & Spradling, A. C. (2005) · Nature · doi:10.1038/nature04333 · Cited by 1,089
DasGupta, R., & Fuchs, E. V. (1999) · Development · doi:10.1242/dev.126.20.4557 · Cited by 995
Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration
Ding, B., Nolan, D. J., Butler, J. M., James, D., Babazadeh, A. O., Rosenwaks, Z., Mittal, V., Kobayashi, H., Shido, K., Lyden, D. C., et al. (2010) · Nature · doi:10.1038/nature09493 · Cited by 853
Bänziger, C., Soldini, D., Schütt, C., Zipperlen, P., Hausmann, G., & Basler, K. (2006) · Cell · doi:10.1016/j.cell.2006.02.049 · Cited by 764
Zonation of parenchymal and nonparenchymal metabolism in liver.
Jungermann, K., & Keitzmann, T. (1996) · Annual Review of Nutrition · doi:10.1146/annurev.nu.16.070196.001143 · Cited by 589
Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming
Miyajima, A., Tanaka, M., & Itoh, T. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.04.010 · Cited by 570
Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver
Benhamouche, S., Decaens, T., Godard, C., Chambrey, R., Rickman, D. S., Moinard, C., Vasseur-Cognet, M., Kuo, C. J., Kahn, A., Perret, C., et al. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.03.015 · Cited by 543
The ploidy conveyor of mature hepatocytes as a source of genetic variation
Duncan, A. W., Taylor, M. H., Hickey, R. D., Hanlon Newell, A. E., Lenzi, M. L., Olson, S. B., Finegold, M. J., & Grompe, M. (2010) · Nature · doi:10.1038/nature09414 · Cited by 525
van Amerongen, R., Bowman, A. N., & Nusse, R. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.05.023 · Cited by 454
Self-citationFate tracing of mature hepatocytes in mouse liver homeostasis and regeneration
Malato, Y., Naqvi, S., Schürmann, N., Ng, R., Wang, B., Zape, J., Kay, M. A., Grimm, D., & Willenbring, H. (2011) · Journal of Clinical Investigation · doi:10.1172/jci59261 · Cited by 434
Self-citationAdult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation
Yanger, K., Knigin, D., Zong, Y., Maggs, L., Gu, G., Akiyama, H., Pikarsky, E., & Stanger, B. Z. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.06.003 · Cited by 426
New targets of β-catenin signaling in the liver are involved in the glutamine metabolism
Cadoret, A., Ovejero, C., Terris, B., Souil, E., Lévy, L., Lamers, W. H., Kitajewski, J., Kahn, A., & Perret, C. (2002) · Oncogene · doi:10.1038/sj.onc.1206118 · Cited by 412
Zeng, Y. A., & Nusse, R. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.03.020 · Cited by 407
Self-citationKreamer, B. L., Staecker, J. L., Sawada, N., Sattler, G. L., Hsia, M. T. S., & Pitot, H. C. (1986) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02623304 · Cited by 383
Interfollicular Epidermal Stem Cells Self-Renew via Autocrine Wnt Signaling
Lim, X., Tan, S. H., Koh, W. L. C., Chau, R. M. W., Yan, K. S., Kuo, C. J., van Amerongen, R., Klein, A. M., & Nusse, R. (2013) · Science · doi:10.1126/science.1239730 · Cited by 357
Self-citationGenetics of hepatocellular tumors
Laurent‐Puig, P., & Zucman‐Rossi, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209547 · Cited by 317
Liver Cell Polyploidization: A Pivotal Role for Binuclear Hepatocytes
Guidotti, J.-E., Brégerie, O., Robert, A., Debey, P., Brechot, C., & Desdouets, C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300982200 · Cited by 315
Mitotic and mitogenic Wnt signalling
Niehrs, C., & Acebron, S. P. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.124 · Cited by 305
Wang, R., Ferrell, L. D., Faouzi, S., Maher, J. J., & Bishop, J. M. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.5.1023 · Cited by 291
Tbx3 improves the germ-line competency of induced pluripotent stem cells
Han, J., Yuan, P., Yang, H., Zhang, J., Soh, B. S., Li, P., Lim, S. L., Cao, S., Tay, J., Orlov, Y. L., et al. (2010) · Nature · doi:10.1038/nature08735 · Cited by 285
Zajicek, G., Oren, R., & Weinreb, M. M. (1985) · Liver International · doi:10.1111/j.1600-0676.1985.tb00252.x · Cited by 273
VE‐cadherin‐CreER T2 transgenic mouse: A model for inducible recombination in the endothelium
Monvoisin, A., Alva, J. A., Hofmann, J. J., Zovein, A. C., Lane, T. F., & Iruela‐Arispe, M. L. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20982 · Cited by 255
Differential gene expression in periportal and perivenous mouse hepatocytes
Braeuning, A., Ittrich, C., Köhle, C., Hailfinger, S., Bonin, M., Buchmann, A., & Schwarz, M. (2006) · The FEBS Journal · doi:10.1111/j.1742-4658.2006.05503.x · Cited by 240
Sigal, S. H., Rajvanshi, P., Gorla, G. R., Sokhi, R. P., Saxena, R., Gebhard, D. R., Reid, L. M., & Gupta, S. K. (1999) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1999.276.5.g1260 · Cited by 230
Distinct pathways of genomic progression to benign and malignant tumors of the liver
Tward, A. D., Jones, K. D., Yant, S. R., Cheung, S., Fan, S. T., Chen, X., Kay, M. A., Wang, R., & Bishop, J. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706578104 · Cited by 217
Tan, X., Yuan, Y., Zeng, G., Apte, U., Thompson, M. D., Cieply, B., Stolz, D. B., Michalopoulos, G. K., Kaestner, K. H., & Monga, S. P. S. (2008) · Hepatology · doi:10.1002/hep.22225 · Cited by 202
Limiting the Proliferation of Polyploid Cells
Ganem, N. J., & Pellman, D. S. (2007) · Cell · doi:10.1016/j.cell.2007.10.024 · Cited by 174
Generation of mice with a conditional null allele for Wntless
Carpenter, A. C., Rao, S., Wells, J. M., Campbell, K., & Lang, R. A. (2010) · genesis · doi:10.1002/dvg.20651 · Cited by 148
Suzuki, A., Sekiya, S., Büscher, D., Izpisúa Belmonte, J. C., & Taniguchi, H. (2008) · Development · doi:10.1242/dev.016634 · Cited by 136 · cited 2×
“The stem cell marker Tbx3 is expressed widely in early liver hepatoblasts and is important for hepatoblast proliferation and initiation of hepatocyte differentiation[19, 37].”
BackgroundVijayakumar, S., Liu, G., Rus, I. A., Yao, S., Chen, Y., Akiri, G., Grumolato, L., & Aaronson, S. A. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.010 · Cited by 128
Cell proliferation and renewal of normal hepatocytes and bile duct cells in adult mouse liver
Magami, Y., Azuma, T., Inokuchi, H., Kokuno, S., Moriyasu, F., Kawai, K., & Hattori, T. (2002) · Liver International · doi:10.1034/j.1600-0676.2002.01702.x · Cited by 124
Lüdtke, T. H. ‐., Christoffels, V. M., Petry, M., & Kispert, A. (2009) · Hepatology · doi:10.1002/hep.22700 · Cited by 117
Emergence of a population of small, diploid hepatocytes during hepatocarcinogenesis
Schwarze, P. E., Pettersen, E. O., Shoaib, M. C., & Seglen, P. O. (1984) · Carcinogenesis · doi:10.1093/carcin/5.10.1267 · Cited by 95
Impaired neural development caused by inducible expression of Axin in transgenic mice
Yu, H. I., Liu, B., Costantini, F. D., & Hsu, W. (2006) · Mechanisms of Development · doi:10.1016/j.mod.2006.10.002 · Cited by 60
Moreira, P. I., Custódio, J. B. A., NUNES, E., Moreno, A. J., Seiça, R. M. F., Oliveira, C. R., & Santos, M. S. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.02.006 · Cited by 24
Emergence of a population of small diploid hepatocytes during hepatocarcinogenesis
Schwarze, P. E., Pettersen, E. P., Shoaib, M. C., & Seglen, P. O. (1985) · Food and Chemical Toxicology · doi:10.1016/0278-6915(85)90308-4 · Cited by 13
Streaming liver VII: DNA turnover in acinus zone‐3
Zajicek, G., & Schwartz‐Arad, D. (1990) · Liver International · doi:10.1111/j.1600-0676.1990.tb00448.x · Cited by 6
Flagged first, then by citations
Cited by
Sorted by citations
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
Michalopoulos, G. K., & Bhushan, B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0342-4 · Cited by 998
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
