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Cited by 102Liver physiology and pathologyHepatocellular Carcinoma Treatment and PrognosisWnt/β-catenin signaling in development and cancer

Lgr5 + pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis

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Ang, Chow Hiang, Hsu, Shih Han, Guo, Fusheng, Tan, Chong Teik, Yu, Victor C., Visvader, Jane E., Chow, Pierce K. H., Fu, Nai Yang·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1908099116PMC PMC6765306
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Abstract

Significance: Liver has a remarkable regenerative capacity following injuries. However, the cellular dynamics of how hepatocytes are replenished during homeostasis and upon liver injuries remains largely unclear. By using genetic lineage tracing strategies on rare Lgr5 + hepatocytes surrounding the central veins of the liver lobule, this study shows that Lgr5 + hepatocytes are self-maintained during normal homeostasis and various liver injuries, and contributed to hepatocarcinogesis in two different hepatocellular carcinoma (HCC) models. Our findings provide an insight on hepatocyte regeneration under homeostasis and liver injuries and uncover Lgr5 + hepatocytes as potential cellular origin in HCC development.

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Crossref · 10.1073/pnas.1908099116

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  • Due to high levels of WNT/β-catenin signalling, pericentral hepatocytes express the β-catenin target gene Lgr5, which confers tissue stem cell identity in the gut, but not in the liver.

    “Due to high levels of WNT/β-catenin signalling, pericentral hepatocytes express the β-catenin target gene Lgr5, which confers tissue stem cell identity in the gut, but not in the liver.44,50”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [50]

    The Discussion (page unavailable) identifies Lgr5 as a Wnt target gene expressed in hepatocytes adjacent to central veins, and the Abstract reports that these cells mainly maintain their own lineage during normal liver regeneration. The Results call Lgr5 a stem-cell marker in epithelial tissues, but this paper does not establish that Lgr5 confers stem-cell identity in the gut or that high Wnt signalling causes its expression in pericentral hepatocytes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours, and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.

    “Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.50,90,91,85”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [50]

    The Discussion reports constitutive WNT-pathway activation in approximately 50% of HCC patients. The Results and Discussion show that Lgr5+ pericentral hepatocytes, which express WNT target genes, are highly susceptible to transformation in the DEN and Neu/Her2 mouse models. The paper does not establish that hepatocytes with high WNT/β-catenin activity generally share that susceptibility; the tested population was the narrower Lgr5+ subset. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Previous studies have shown that cells in zone 3 can transform into HCC.

    “Previous studies have shown that cells in zone 3 can transform into HCC (22–24), but there has not been a head-to-head comparison to assess cancer formation from different zones.”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [24]

  • 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.

    “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 [50]

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Cited by

Sorted by citations

Authors
Ang, C. H., Hsu, S. H., Guo, F., Tan, C. T., Yu, V. C., Visvader, J. E., Chow, P. K. H., & Fu, N. Y.
Affiliations
  • National University of Singapore (SG)
  • The University of Melbourne (AU)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-09-05
Volume
116
Issue
39
Pages
19530-19540
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1908099116
PMC
PMC6765306
OpenAlex
W2971915501
Cited by
102
References
11
Citations by year
2026: 6 · 2025: 13 · 2024: 17 · 2023: 19 · 2022: 11 · 2021: 21 · 2020: 13 · 2019: 1 · 2018: 1
FWCI
7.33
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Khoo Postdoctoral Fellowship Award (R-913-303-081-592)
  • Duke-NUS Faculty Start-up Fund (R-913-200-115-263)
  • Khoo Bridge Funding Award (R-913-303-062-592)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
Lgr5, pericentral hepatocytes, liver regeneration, hepatocarcinogenesis, hepatocellular carcinoma, liver injury, liver homeostasis, cancer stem cells
MeSH terms
Animals, Cell Differentiation, Disease Models, Animal, Female, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Liver Regeneration, Male, Mice, Transgenic, Stem Cells, Cell Lineage, Hepatocytes, Receptors, G-Protein-Coupled, Cell Proliferation, Mice

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