The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Broad Distribution of Hepatocyte Proliferation in Liver Homeostasis and Regeneration
Open accessAbstract
Hepatocyte proliferation is the principal mechanism for generating new hepatocytes in liver homeostasis and regeneration. Recent studies have suggested that this ability is not equally distributed among hepatocytes but concentrated in a small subset of hepatocytes acting like stem cells, located around the central vein or distributed throughout the liver lobule and exhibiting active WNT signaling or high telomerase activity, respectively. These findings were obtained by utilizing components of these growth regulators as markers for genetic lineage tracing. Here, we used random lineage tracing to localize and quantify clonal expansion of hepatocytes in normal and injured liver. We found that modest proliferation of hepatocytes distributed throughout the lobule maintains the hepatocyte mass and that most hepatocytes proliferate to regenerate it, with diploidy providing a growth advantage over polyploidy. These results show that the ability to proliferate is broadly distributed among hepatocytes rather than limited to a rare stem cell-like population.
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
“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 [88]
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 [88]
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 [14]
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 [88]
The cited source says what the claim attributes to it.
In the citing paper
“3D imaging of labelled cells and their progeny showed that hepatocyte renewal is not driven by zone 3, no hepatocytes formed particularly large clones, and hepatocyte proliferation was distributed throughout the lobule with larger hepatocyte clones more frequently found in zone 2.88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
The cited source says what the claim attributes to it.
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 [88]
The cited source says what the claim attributes to it.
In the citing paper
“However, ∼80% of hepatocytes randomly labelled by AAV8-TBG-Cre gave rise to expanding hepatocyte clones in mouse livers subjected to repeated CCl4 injury, indicating that proliferative hepatocytes are relatively abundant.88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
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
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890
Advanced CUBIC protocols for whole-brain and whole-body clearing and imaging
Susaki, E. A., Tainaka, K., Perrin, D., Yukinaga, H., Kuno, A., & Ueda, H. R. (2015) · Nature Protocols · doi:10.1038/nprot.2015.085 · Cited by 822
Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
Wang, B., Zhao, L., Fish, M., Logan, C. Y., & Nusse, R. (2015) · Nature · doi:10.1038/nature14863 · Cited by 674
Coronary arteries form by developmental reprogramming of venous cells
Red‐Horse, K., Ueno, H., Weissman, I. L., & Krasnow, M. A. (2010) · Nature · doi:10.1038/nature08873 · Cited by 550
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
Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer
Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A., Taniguchi, K., Nakagawa, H., Valasek, M. A., Ye, L., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.026 · Cited by 486
Luche, H., Weber, O., Nageswara Rao, T., Blum, C., & Fehling, H. J. (2007) · European Journal of Immunology · doi:10.1002/eji.200636745 · Cited by 482
Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration
Miyaoka, Y., Ebato, K., Kato, H., Arakawa, S., Shimizu, S., & Miyajima, A. (2012) · Current Biology · doi:10.1016/j.cub.2012.05.016 · Cited by 461
Adult 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
Conditional telomerase induction causes proliferation of hair follicle stem cells
Sarin, K. Y., Cheung, P., Gilison, D., Lee, E., Tennen, R. I., Wang, E., Artandi, M. K., Oro, A. E., & Artandi, S. E. (2005) · Nature · doi:10.1038/nature03836 · Cited by 425
Flagged first, then by citations
Cited by
Sorted by citations
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
Kumar, S., Duan, Q., Wu, R., Harris, E. N., & Su, Q. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113869 · Cited by 382
Liver regeneration and inflammation: from fundamental science to clinical applications
Campana, L., Esser, H., Huch, M., & Forbes, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00373-7 · Cited by 307
Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Wei, Y., Wang, Y. G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., et al. (2021) · Science · doi:10.1126/science.abb1625 · Cited by 292
Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair
He, L., Pu, W., Liu, X., Zhang, Z., Han, M., Li, Y., Huang, X., Han, X., Li, Y., Liu, K., et al. (2021) · Science · doi:10.1126/science.abc4346 · Cited by 261
Metadata
- Authors
- Chen, F., Jimenez, R. J., Sharma, K., Luu, H. Y., Hsu, B. Y., Ravindranathan, A., Stohr, B. A., & Willenbring, H.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Chen, Feng
- Willenbring, Holger
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 26
- Issue
- 1
- Pages
- 27-33.e4
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC8009755
- OpenAlex
- W2996029077
- Cited by
- 236
- References
- 21
- Citations by year
- 2026: 15 · 2025: 32 · 2024: 34 · 2023: 51 · 2022: 34 · 2021: 44 · 2020: 26
- FWCI
- 16.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Eli and Edythe Broad Foundation (R01 AA026578, CIRM DISC2-10088)
- California Institute of Regenerative Medicine
- National Institutes of Health (P30 DK026743, R01 AA026578, T32 DK060414)
- Novartis
- Jane Coffin Childs Memorial Fund for Medical Research
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- hepatocyte proliferation, liver homeostasis, liver regeneration, clonal expansion, Wnt signaling, telomerase, polyploidy, diploidy, liver lobule
- MeSH terms
- Homeostasis, Liver, Liver Regeneration, Hepatocytes, Cell Proliferation
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
