Cited by 241Liver physiology and pathologyMesenchymal stem cell researchTelomeres, Telomerase, and Senescence

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Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury

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Lin, Shengda, Nascimento, Elisabete M., Gajera, Chandresh R., Chen, Lu, Neuhöfer, Patrick, Garbuzov, Alina, Wang, Sui, Artandi, Steven E.·2018·Nature

DOI 10.1038/s41586-018-0004-7PMC PMC5895494

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Abstract

Hepatocytes are replenished gradually during homeostasis and robustly after liver injury 1, 2. In adults, new hepatocytes originate from the existing hepatocyte pool 3-8, but the cellular source of renewing hepatocytes remains unclear. Telomerase is expressed in many stem cell populations, and mutations in telomerase pathway genes have been linked to liver diseases 9-11. Here we identify a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury. Using lineage tracing from the telomerase reverse transcriptase (Tert) locus in mice, we demonstrate that rare hepatocytes with high telomerase expression (TERT High hepatocytes) are distributed throughout the liver lobule. During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver. In response to injury, the repopulating activity of TERT High hepatocytes is accelerated and their progeny cross zonal boundaries. RNA sequencing shows that metabolic genes are downregulated in TERT High hepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage. Genetic ablation of TERT High hepatocytes combined with chemical injury causes a marked increase in stellate cell activation and fibrosis. These results provide support for a 'distributed model' of hepatocyte renewal in which a subset of hepatocytes dispersed throughout the lobule clonally expands to maintain liver mass.

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Authors: Lin, S., Nascimento, E. M., Gajera, C. R., Chen, L., Neuhöfer, P., Garbuzov, A., Wang, S., & Artandi, S. E.
Affiliations: Stanford Medicine (US)
Corresponding author: Artandi, Steven E.
ORCID: Lin, Shengda
Gajera, Chandresh R.
Neuhöfer, Patrick
Wang, Sui
Artandi, Steven E.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-04
Volume: 556
Issue: 7700
Pages: 244-248
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0004-7
PMC: PMC5895494
OpenAlex: W2794622099
Cited by: 241
References: 40
Citations by year: 2026: 9 · 2025: 24 · 2024: 20 · 2023: 32 · 2022: 28 · 2021: 38 · 2020: 42 · 2019: 29 · 2018: 19
FWCI: 20.05
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
TUScholarShare (Temple University) (submittedVersion)
Funders: National Institute on Aging (R01AG056575)
National Cancer Institute (R35CA197563)
National Institute of Neurological Disorders and Stroke (P30NS069375)
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords: telomerase, liver regeneration, liver injury, liver homeostasis, hepatocyte differentiation, stellate cell activation, liver fibrosis, lineage tracing, clonal expansion
MeSH terms: Cell Self Renewal, Animals, Female, Homeostasis, Liver, Liver Regeneration, Male, Sequence Analysis, RNA, Cell Lineage, Telomerase, Hepatocytes, Mice

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Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury

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