Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury
Open accessAbstract
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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Rare distributed high telomerase-expressing hepatocytes are highly regenerative, giving rise to 38% of the parenchyma after 1 month of DDC-induced injury.
“Rare distributed high telomerase-expressing hepatocytes were observed to be highly regenerative, giving rise to 38% of the parenchyma after 1 month of DDC-induced injury89”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [89]
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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.
- Venue
- Nature
- Published
- 2018-04
- Volume
- 556
- Issue
- 7700
- Pages
- 244-248
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Physiology › 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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