The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Open accessAbstract
Zoning in on liver growth: For organ homeostasis or regrowth after injury or disease, one or more stem cell populations is needed to rebuild lost tissue. There is considerable debate about the source of new cells in the liver. Two groups now identify the source of new hepatocytes (see the Perspective by Andersson). Although the liver may seem to lack major variation across its structure, its lobule is organized into concentric zones where hepatocytes express different metabolic enzymes. Wei et al. sought to systematically define the source of new liver cells by comparing 14 fate-mapping mice that label different liver cell types. They found that different regions of the liver lobule exhibit differences in hepatocyte turnover, with zone 2 representing a primary source of new hepatocytes during homeostasis and regeneration. Similarly, He et al. designed a genetic approach to record cell proliferation in vivo with high spatial and temporal resolution to enable continuous recording of proliferative events of any specific cell type at the whole-cell population level. Using this method, they identified zone 2 as having the highest proliferative activity and contributing the most to liver regrowth. These findings have implications for the cellular basis of chronic disease pathogenesis, cancer development, and regenerative medicine strategies. Science , this issue p. eabb1625 , p. eabc4346 ; see also p. 887
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
“To annotate clusters by zone and cell type, known marker genes were used (18), including markers for hepatic zones (zone-specific genes), bile duct cells, Kupffer cells, endothelial cells, hepatic stellate cells, and lymphocytes.”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [18]
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
“Instead, EdU incorporation suggested that knocking CreERT2 into the endogenous Axin2 locus increases proliferation of hepatocytes due to heterozygous Axin2 deletion.86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
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
“Additionally, sparsely labelled hepatocytes, marked by novel Cre-expressing transgenes from the Hamp2 and Mup3 promoters, also expanded during homeostasis, demonstrating that proliferation is not limited to the high telomerase-expressing population.86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
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
“Additionally, injury to zone 1 by allyl alcohol injection or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet was compensated by proliferation of hepatocytes in zones 2 and 3.85,86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
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
“Zone 2 hepatocytes labelled by AAV8-TBG-Cre or CreERT2 expressed from the Hamp2 or Mup3 promoters also proliferated and clonally expanded.86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
Experimental — accuracy not yet measured
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
“Additionally, hepatocytes traced from the Hamp2 and Mup3 promoters readily gave rise to hepatocyte clusters after CCl4 and DDC injury.86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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 [18]
The cited source says what the claim attributes to it.
In the citing paper
“Analysis using qPCR and IHC suggested that this effect was mediated by RSPO3-dependent regulation of the WNT target CCND1 (Fig. 4a and Extended Data Figs. 7a and 10b), a key driver of liver regeneration23,42.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [42]
The cited source says what the claim attributes to it.
In the citing paper
“Corresponding to the predominantly midzonal alterations in WNT-target genes as a result of a condensed zone 3 and an expanded zone 1 (Fig. 3i and Extended Data Fig. 8c), the alterations in proliferation and liver injury in Rspo3ΔHSC mice were most pronounced in the hepatic midzone (Fig. 4e and Extended Data Fig. 10b), which is pivotal for hepatocyte regeneration42.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [42]
The cited source says what the claim attributes to it.
In the citing paper
“The recent generation of mice with Cre recombinase activity in distinct zonal populations permitted us to induce HCC mutations in a variety of normal cell types (18).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“Cyp1a2-CreER mice recombine loci in zones 2 and 3, but more frequently in zone 3 (18).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“During homeostasis, zone 2 hepatocytes rather than a defined subpopulation seem to have increased proliferative potential.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“Nevertheless, hepatocytes do not proliferate equally over time, as results obtained via three independent experimental approaches have led to the same conclusion, namely that zone 2 hepatocytes proliferate more than hepatocytes from the other zones.75,86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“Hepatocyte proliferation in zone 2 hepatocytes is mediated by the IGFBP2-mTOR-CCND1 axis.86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“A comprehensive study using several new mouse transgenic lines to label different portions of the lobule also demonstrated that zone 2 hepatocytes expand during homeostasis, with a corresponding contraction of the areas originally occupied by zone 1 or 3 hepatocytes.86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“Alternative zone 3 labelling with other gene promoters also did not show that zone 3 hepatocytes give rise to hepatocytes in other zones during homeostasis.44,50,86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [86]
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
Fast unfolding of communities in large networks
Blondel, V. D., Guillaume, J.-L., Lambiotte, R., & Lefebvre, E. (2008) · Journal of Statistical Mechanics: Theory and Experiment · doi:10.1088/1742-5468/2008/10/p10008 · Cited by 21,424
SCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881
From Louvain to Leiden: guaranteeing well-connected communities
Traag, V. A., Waltman, L., & van Eck, N. J. (2019) · Scientific Reports · doi:10.1038/s41598-019-41695-z · Cited by 5,635
Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors
Haghverdi, L., Lun, A. T. L., Morgan, M. D., & Marioni, J. C. (2018) · Nature Biotechnology · doi:10.1038/nbt.4091 · Cited by 2,416
Epidemiology and Management of Hepatocellular Carcinoma
Kulik, L., & El‐Serag, H. B. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.08.065 · Cited by 1,764
Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations
MacParland, S. A., Liu, J. C., Ma, X.-Z., Innes, B. T., Bartczak, A. M., Gage, B. K., Manuel, J., Khuu, N., Echeverri, J., Linares, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06318-7 · Cited by 1,552
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
Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.722 · Cited by 841
Sadana, P., Geyer, R., Pezoldt, J., Helmsing, S., Huehn, J., Hust, M., Dersch, P., & Scrima, A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001068 · Cited by 721
Flagged first, then by citations
Cited by
Sorted by citations
Andrews, T. S., Atif, J., Liu, J. C., Perciani, C. T., Ma, X., Thoeni, C., Slyper, M., Eraslan, G., Segerstolpe, A., Manuel, J., et al. (2022) · Hepatology Communications · doi:10.1002/hep4.1854 · Cited by 307
The spatiotemporal program of zonal liver regeneration following acute injury
Ben-Moshe, S., Veg, T., Manco, R., Dan, S., Papinutti, D., Lifshitz, A., Kolodziejczyk, A. A., Bahar Halpern, K., Elinav, E., & Itzkovitz, S. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.04.008 · Cited by 224
The Hippo signaling pathway in development and regeneration
Zhong, Z., Jiao, Z., & Yu, F. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113926 · Cited by 223
Amino acid metabolism, transport and signalling in the liver revisited
Paulusma, C. C., Lamers, W. H., Bröer, S., & van de Graaf, S. F. J. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115074 · Cited by 185
Paris, J., & Henderson, N. C. (2022) · Hepatology · doi:10.1002/hep.32408 · Cited by 177
Metadata
- Authors
- Wei, Y., Wang, Y. G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., Lin, Y.-H., Hsieh, M.-H., Albrecht, J. H., Le, P. T., Rosen, C. J., Wang, T., & Zhu, H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Minnesota (US)
- Maine Medical Center (US)
- Corresponding author
- Zhu, Hao
- ORCID
- Venue
- Science
- Published
- 2021-02-26
- Volume
- 371
- Issue
- 6532
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8496420
- OpenAlex
- W3132549301
- Cited by
- 292
- References
- 43
- Citations by year
- 2026: 37 · 2025: 60 · 2024: 39 · 2023: 73 · 2022: 53 · 2021: 30
- FWCI
- 27.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01 CA251928)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK111588)
- National Institute of Environmental Health Sciences (R03ES026397-01)
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas (RP150596, RP190208)
- Stand Up To Cancer (SU2C-AACR-IRG 10-16)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- liver homeostasis, hepatocyte proliferation, liver regeneration, hepatocyte turnover, fate mapping, cell proliferation imaging, liver stem cells
- MeSH terms
- Animals, Biliary Tract, Biliary Tract Diseases, Homeostasis, Liver, Liver Regeneration, Insulin-Like Growth Factor Binding Protein 2, Cyclin D1, Hepatocytes, Cell Proliferation, Mice, Gene Knock-In Techniques, TOR Serine-Threonine Kinases
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
