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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 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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Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
ggplot2: Elegant Graphics for Data Analysis
Wickham, H. (2009) · doi:10.1007/978-0-387-98141-3 · Cited by 14,447
Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., & Salzberg, S. L. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r36 · Cited by 12,668
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,927
Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
Gao, G.-P., Alvira, M. R., Wang, L., Calcedo, R., Johnston, J., & Wilson, J. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182412299 · Cited by 1,520
Zolotukhin, S., Byrne, B. J., Mason, E. G., Zolotukhin, I., Potter, M., Chesnut, K. A., Summerford, C., Samulski, R. J., & Muzyczka, N. (1999) · Gene Therapy · doi:10.1038/sj.gt.3300938 · Cited by 1,321
Mechanisms of carbon tetrachloride toxicity
Recknagel, R. O., Glende, E. A., Dolak, J. A., & Waller, R. L. (1989) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(89)90050-8 · Cited by 1,234
Nault, J., Mallet, M., Pilati, C., Caldéraro, J., Bioulac‐Sage, P., Laurent, C., Laurent, A., Cherqui, D., Balabaud, C. P., & Zucman‐Rossi, J. (2013) · Nature Communications · doi:10.1038/ncomms3218 · Cited by 691
Kim, N. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.13.2595 · Cited by 688
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
Galanin neurons in the medial preoptic area govern parental behaviour
Wu, Z., Autry, A. E., Bergan, J. F., Watabe‐Uchida, M., & Dulac, C. G. (2014) · Nature · doi:10.1038/nature13307 · Cited by 610
Generation and Regeneration of Cells of the Liver and Pancreas
Zaret, K. S., & Grompe, M. (2008) · Science · doi:10.1126/science.1161431 · Cited by 598
Zonation of parenchymal and nonparenchymal metabolism in liver.
Jungermann, K., & Keitzmann, T. (1996) · Annual Review of Nutrition · doi:10.1146/annurev.nu.16.070196.001143 · Cited by 589
Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells
Montgomery, R. K., Carlone, D. L., Richmond, C. A., Farilla, L., Kranendonk, M. E. G., Henderson, D. E., Baffour‐Awuah, N. Y., Ambruzs, D. M., Fogli, L. K., Algra, S. O., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013004108 · Cited by 566
Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes
Tarlow, B. D., Pelz, C., Naugler, W. E., Wakefield, L., Wilson, E. M., Finegold, M. J., & Grompe, M. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.09.008 · Cited by 533
Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration
Raven, A., Lu, W.-Y., Man, T. Y., Ferreira-Gonzalez, S., O’Duibhir, E., Dwyer, B. J., Thomson, J. P., Meehan, R. R., Bogorad, R., Koteliansky, V., et al. (2017) · Nature · doi:10.1038/nature23015 · Cited by 533
Aurnhammer, C., Haase, M., Müther, N., Mück-Häusl, M., Rauschhuber, C., Huber, I., Nitschko, H., Busch, U., Sing, A., Ehrhardt, A., et al. (2012) · Human Gene Therapy Methods · doi:10.1089/hgtb.2011.034 · Cited by 494
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
Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration
Malato, Y., Naqvi, S., Schürmann, N., Ng, R., Wang, B., Zape, J., Kay, M. A., Grimm, D., & Willenbring, H. (2011) · Journal of Clinical Investigation · doi:10.1172/jci59261 · Cited by 434
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
Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery
Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N., & DePinho, R. A. (2000) · Science · doi:10.1126/science.287.5456.1253 · Cited by 424
The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size
Planas-Paz, L., Orsini, V., Boulter, L., Calabrese, D., Pikiolek, M., Nigsch, F., Xie, Y., Roma, G., Donovan, A., Marti, P., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3337 · Cited by 359
Single-molecule transcript counting of stem-cell markers in the mouse intestine
Itzkovitz, S., Lyubimova, A., Blat, I. C., Maynard, M. A., van Es, J. H., Lees, J. A., Jacks, T., Clevers, H. C., & van Oudenaarden, A. (2011) · Nature Cell Biology · doi:10.1038/ncb2384 · Cited by 352
Schaub, J. R., Malato, Y., Gormond, C., & Willenbring, H. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.003 · Cited by 254
Cellular Homeostasis and Repair in the Mammalian Liver
Stanger, B. Z. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170255 · Cited by 248
Clonal Tracing of Sox9+ Liver Progenitors in Mouse Oval Cell Injury
Tarlow, B., Finegold, M. J., & Grompe, M. (2014) · Hepatology · doi:10.1002/hep.27084 · Cited by 224
Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes
Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M., & Clevers, H. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.26 · Cited by 217
Elias, H. (1949) · American Journal of Anatomy · doi:10.1002/aja.1000850303 · Cited by 196
Constitutional telomerase mutations are genetic risk factors for cirrhosis
Calado, R. T., Brudno, J. N., Chaudhry, P. M., Kovacs, J. J., Wu, C. O., Zago, M. A., Chanock, S. J., BOYER, T. D., & Young, N. S. (2011) · Hepatology · doi:10.1002/hep.24173 · Cited by 195
Stem cells versus plasticity in liver and pancreas regeneration
Kopp, J. L., Grompe, M., & Sander, M. (2016) · Nature Cell Biology · doi:10.1038/ncb3309 · Cited by 176
Telomerase gene mutations are associated with cirrhosis formation
Hartmann, D., Srivastava, U., Thaler, M., Kleinhans, K. N., N'Kontchou, G., Scheffold, A., Bauer, K., Kratzer, R. F., Kloos, N., Katz, S.-F., et al. (2011) · Hepatology · doi:10.1002/hep.24217 · Cited by 173
qPrimerDepot: a primer database for quantitative real time PCR
Cui, W., Taub, D. D., & Gardner, K. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl767 · Cited by 158
Wu, S., Ying, G., Wu, Q., & Capecchi, M. R. (2008) · Nature Protocols · doi:10.1038/nprot.2008.70 · Cited by 133
Dynamic zonation of liver polyploidy
Tanami, S., Ben-Moshe, S., Elkayam, A., Mayo, A., Bahar Halpern, K., & Itzkovitz, S. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2427-5 · Cited by 77
Pech, M. F., Garbuzov, A., Hasegawa, K., Sukhwani, M., Zhang, R. J., Benayoun, B. A., Brockman, S. A., Lin, S., Brunet, A., Orwig, K. E., et al. (2015) · Genes & Development · doi:10.1101/gad.271783.115 · Cited by 74
Self-citationSnippert, H. J. G., Schepers, A. G., Delconte, G., Siersema, P. D., & Clevers, H. C. (2011) · Nature Protocols · doi:10.1038/nprot.2011.365 · Cited by 47
Understanding telomere diseases through analysis of patient-derived iPS cells
Batista, L. F. Z., & Artandi, S. E. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.07.006 · Cited by 35
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Michalopoulos, G. K., & Bhushan, B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0342-4 · Cited by 998
Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids
Hu, H., Gehart, H., Artegiani, B., LÖpez-Iglesias, C., Dekkers, F., Basak, O., van Es, J., Chuva de Sousa Lopes, S. M., Begthel, H., Korving, J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.013 · Cited by 837
Molecular pathogenesis and systemic therapies for hepatocellular carcinoma
Llovet, J. M., Pinyol, R., Kelley, R. K., El-Khoueiry, A., Reeves, H. L., Wang, X. W., Gores, G. J., & Villanueva, A. (2022) · Nature Cancer · doi:10.1038/s43018-022-00357-2 · Cited by 498
Inverse Association of Telomere Length With Liver Disease and Mortality in the US Population
Rattan, P., Penrice, D. D., Ahn, J. C., Ferrer, A., Patnaik, M. M., Shah, V. H., Kamath, P. S., Mangaonkar, A. A., & Simonetto, D. A. (2021) · Hepatology Communications · doi:10.1002/hep4.1803 · Cited by 365
Regulation of human telomerase in homeostasis and disease
Roake, C. M., & Artandi, S. E. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0234-z · Cited by 356
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Metadata
- 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
- 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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