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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.
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“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.
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“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]
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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 [14]
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“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]
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“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]
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“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]
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“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]
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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
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