Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration
Open accessAbstract
BACKGROUND & AIMS: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail. METHODS: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in-depth phenotypic comparisons, including transcriptomics, metabolomics and analysis of proteins through immunohistochemistry, of Axin2CreERT2 mice to WT counterparts. RESULTS: We found that after careful definition of a baseline population, there are marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We found substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/β-catenin signalling and related metabolomic disturbance. CONCLUSIONS: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci. IMPACT AND IMPLICATIONS: Understanding the source of cells which regenerate the liver is crucial to harness their potential to regrow injured livers. Herein, we show that cells which were previously thought to repopulate the liver play only a limited role in physiological regeneration. Our data helps to reconcile differing conclusions drawn from results from a number of prior studies and highlights methodological challenges which are relevant to preclinical models more generally.
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Independent validation using the original Axin2-CreERT2 mouse line in a new study did not replicate expansion of the labelled hepatocytes into other zones.
“Finally, independent validation using the original Axin2-CreERT2 mouse line in a new study did not replicate expansion of the labelled hepatocytes into other zones.87”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [87]
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The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000410 · Cited by 5,939 · see citing works
Functional Interaction of an Axin Homolog, Conductin, with β-Catenin, APC, and GSK3β
Behrens, J., Jerchow, B., Würtele, M., Grimm, J., Asbrand, C., Wirtz, R. M., Kühl, M., Wedlich, D., & Birchmeier, W. (1998) · Science · doi:10.1126/science.280.5363.596 · Cited by 1,255 · see citing works
The ARRIVE guidelines 2019: updated guidelines for reporting animal researchPreprint
du Sert, N. P., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/703181 · Cited by 1,042 · see citing works
Liver regeneration: biological and pathological mechanisms and implications
Michalopoulos, G. K., & Bhushan, B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0342-4 · Cited by 998 · see citing works
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 · see citing works
The ARRIVE guidelines 2.0: updated guidelines for reporting animal research
du Sert, N. P., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., et al. (2020) · The Journal of Physiology · doi:10.1113/jp280389 · Cited by 623 · see citing works
Wnt–β-catenin signalling in liver development, health and disease
Perugorria, M. J., Olaizola, P., Labiano, I., Esparza-Baquer, A., Marzioni, M., Marı́n, J. J. G., Bujanda, L., & Bañales, J. M. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0075-9 · Cited by 606 · see citing works
Conditional Deletion of β-Catenin Reveals Its Role in Liver Growth and Regeneration
Tan, X., Behari, J., Cieply, B., Michalopoulos, G. K., & Monga, S. P. S. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.08.042 · Cited by 361 · see citing works
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 · see citing works
Ferrer‐Vaquer, A., Piliszek, A., Tian, G., Aho, R., Dufort, D., & Hadjantonakis, A. (2010) · BMC Developmental Biology · doi:10.1186/1471-213x-10-121 · Cited by 299 · see citing works
Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Wei, Y., Wang, Y. G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., et al. (2021) · Science · doi:10.1126/science.abb1625 · Cited by 292 · see citing works
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He, L., Pu, W., Liu, X., Zhang, Z., Han, M., Li, Y., Huang, X., Han, X., Li, Y., Liu, K., et al. (2021) · Science · doi:10.1126/science.abc4346 · Cited by 261 · see citing works
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Lin, S., Nascimento, E. M., Gajera, C. R., Chen, L., Neuhöfer, P., Garbuzov, A., Wang, S., & Artandi, S. E. (2018) · Nature · doi:10.1038/s41586-018-0004-7 · Cited by 241 · see citing works
AXIN2+ Pericentral Hepatocytes Have Limited Contributions to Liver Homeostasis and Regeneration
Sun, T., Pikiolek, M., Orsini, V., Bergling, S., Holwerda, S., Morelli, L., Hoppe, P. S., Planas-Paz, L., Yang, Y., Ruffner, H., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.10.011 · Cited by 166 · see citing works
β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
Senni, N., Savall, M., Granados, D. C., Alves‐Guerra, M., Sartor, C., Lagoutte, I., Gougèlet, A., Terris, B., Gilgenkrantz, H., Perret, C., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-315448 · Cited by 152 · see citing works
Ma, A. P. Y., Yeung, C. L. S., Tey, S. K., Mao, X., Wong, S. W. K., Ng, T. H., Ko, F. C. F., Kwong, E. M. L., Tang, A. H. N., Ng, I. O., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3944 · Cited by 123 · see citing works
Ang, C. H., Hsu, S. H., Guo, F., Tan, C. T., Yu, V. C., Visvader, J. E., Chow, P. K. H., & Fu, N. Y. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908099116 · Cited by 102 · see citing works
The gut microbiome of laboratory mice: considerations and best practices for translational research
Ericsson, A. C., & Franklin, C. L. (2021) · Mammalian Genome · doi:10.1007/s00335-021-09863-7 · Cited by 85 · see citing works
Sarkar, A., Jin, Y., DeFelice, B. C., Logan, C. Y., Yang, Y., Anbarchian, T., Wu, P. V., Morri, M., Neff, N. F., Nguyen, H., et al. (2022) · eLife · doi:10.7554/elife.82311 · Cited by 23 · see citing works
No Zones Left Behind: Democratic Hepatocytes Contribute to Liver Homeostasis and Repair
Monga, S. P. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.12.002 · Cited by 18 · see citing works
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Rigual, M. D. M., Angulo-Aguado, M., Zagorac, S., Álvarez-Díaz, R., Benítez-Mondéjar, M., Yi, F., Martínez-Garay, C., Santos-de-Frutos, K., Kim, E., Campos-Olivas, R., et al. (2025) · Nature · doi:10.1038/s41586-025-08778-6 · Cited by 53 · see citing works
Region-specific cellular and molecular basis of liver regeneration after acute pericentral injury.
Wang, S., Wang, X., Shan, Y., Tan, Z., Su, Y., Cao, Y., Wang, S., Dong, J., Gu, J., & Wang, Y. (2024) · Cell Stem Cell · doi:10.1016/j.stem.2024.01.013 · Cited by 40 · see citing works
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Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30 · see citing works
Yang, L., Wang, S., Qiao, Z., Liu, Y., Wang, X., Liu, L., Yang, C., Ding, J., Lei, M., Zheng, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64069-8 · Cited by 18 · see citing works
Negative equity – the value of reporting negative results
Sansom, O. J., Bogani, D., Reichenbach, L., & Wells, S. E. (2024) · Disease Models & Mechanisms · doi:10.1242/dmm.050937 · Cited by 13 · see citing works
Self-citationAng, C. H., Arandjelovic, P., Cheng, J., Yang, J., Guo, F., Yu, Y., Nelameham, S., Whitehead, L. W., Li, J., Silver, D. L., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.115093 · Cited by 10 · see citing works
Hepatic zonation determines tumorigenic potential of mutant β-catenin
Raven, A., Gilroy, K. L., Jin, H., Waldron, J. A., Leslie, H., Munro, J., Hall, H., Ridgway, R. A., Ford, C. A., Gulhan, D., et al. (2025) · Nature · doi:10.1038/s41586-025-09733-1 · Cited by 10 · see citing works
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Geng, C., Lin, B., Liu, Y., Sun, K., Yu, M., Liu, H., Feng, H., & Han, D. K. (2025) · BMC Oral Health · doi:10.1186/s12903-025-07232-3 · Cited by 1 · see citing works
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Pennie, R. L., Mason, D., Rakovic, K., Ballantyne, F., Powley, I. R., Γεωργακοπούλου, Α., Bird, T. G., Officer-Jones, L., & Quesne, J. P. C. L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.08.632002
Self-citationBaird, R. L., Mason, D., Rakovic, K., Ballantyne, F., Powley, I. R., Γεωργακοπούλου, Α., Hillary, L., Bird, T. G., Officer-Jones, L., & Quesne, J. P. C. L. (2025) · PLoS ONE · doi:10.1371/journal.pone.0317865
Self-citation
- Authors
- May, S., Müller, M., Livingstone, C. R., Skalka, G. L., Walsh, P. J., Nixon, C., Hedley, A., Shaw, R., Clark, W., Vande Voorde, J., Officer-Jones, L., Ballantyne, F., Powley, I. R., Drake, T. M., Kiourtis, C., Keith, A., Rocha, A. S., Tardito, S., Sumpton, D., Le Quesne, J., Bushell, M., Sansom, O. J., & Bird, T. G.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Corresponding author
- Bird, Thomas G.
- ORCID
- May, Stephanie
- Müller, Miryam
- Livingstone, Callum R.
- Skalka, George L.
- Walsh, Peter J.
- Nixon, Colin
- Hedley, Ann
- Shaw, Robin
- Clark, William
- Vande Voorde, Johan
- Officer-Jones, Leah
- Ballantyne, Fiona
- Powley, Ian R.
- Drake, Thomas M.
- Kiourtis, Christos
- Rocha, Ana Sofia
- Tardito, Saverio
- Sumpton, David
- Le Quesne, John
- Bushell, Martin
- Sansom, Owen J.
- Bird, Thomas G.
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 78
- Issue
- 5
- Pages
- 1028-1036
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W4317726014
- Cited by
- 13
- References
- 19
- Citations by year
- 2025: 7 · 2024: 3 · 2023: 3
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (107492/Z/15/Z, WT107492Z)
- Cancer Research UK (A31287, 24388, A29252, 26813, A25045, A17196/, 29252)
- University of Glasgow
- Biotechnology and Biological Sciences Research Council (BB/M001865/1)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- pericentral hepatocytes, liver regeneration, hepatocyte expansion, Wnt/β-catenin signaling, hepatic metabolomics, liver homeostasis, hepatocyte heterogeneity
- MeSH terms
- Female, Homeostasis, Humans, Liver, Liver Regeneration, Male, Focal Nodular Hyperplasia, Hepatocytes, Cell Proliferation, Axin Protein
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