Loss of hepatocyte cell division leads to liver inflammation and fibrosis
Open accessAbstract
The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.
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In the absence of a capacity for cell division, fibrosis becomes a mode of tissue repair and leads to tissue scarring.
“In the absence of a capacity for cell division, fibrosis becomes a mode of tissue repair and leads to tissue scarring (52, 53).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [52]
The Results (page not provided) report elevated liver fibrosis in mice whose hepatocytes cannot divide, and the Discussion (page not provided) describes a pathway from impaired division to fibrosis. The paper does not establish that fibrosis serves as a mode of tissue repair when cells cannot divide generally, or explicitly describe the resulting fibrosis as tissue scarring. (LLM, conf=0.84)
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Llovet, J. M., Willoughby, C. E., Singal, A. G., Greten, T. F., Heikenwälder, M., El-Serag, H. B., Finn, R. S., & Friedman, S. L. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00754-7 · Cited by 354 · see citing works
Polyploidy in Tissue Repair and RegenerationPreprint
Bailey, E. C., Kobielski, S., Park, J., & Losick, V. P. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a040881 · Cited by 54 · see citing works
Polyploidy control in hepatic health and disease
Sladky, V. C., Eichin, F., Reiberger, T., & Villunger, A. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.06.030 · Cited by 49 · see citing works
Communal living: the role of polyploidy and syncytia in tissue biology
Peterson, N. G., & Fox, D. T. (2021) · Chromosome Research · doi:10.1007/s10577-021-09664-3 · Cited by 47 · see citing works
The role of p53 in liver fibrosis
Yu, S., Ji, G., & Zhang, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1057829 · Cited by 38 · see citing works
Lau, H. W., Ma, H. T., Yeung, T. K., Tam, M. Y., Zheng, D., Chu, S. K., & Poon, R. Y. C. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109808 · Cited by 34 · see citing works
Rodimova, S. A., Mozherov, A. M., Elagin, V. V., Karabut, M. M., Shchechkin, I. D., Kozlov, D., Krylov, D. P., Gavrina, A. I., Bobrov, N., Загайнов, В. Е., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119112 · Cited by 34 · see citing works
Ow, J. R., Caldez, M. J., Zafer, G., Foo, J. C., Li, H. Y., Ghosh, S., Wollmann, H., Cazenave‐Gassiot, A., Ong, C. B., Wenk, M. R., et al. (2020) · eLife · doi:10.7554/elife.63835 · Cited by 31 · see citing works
Self-citationWnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., Peng, W. C., & Nusse, R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203849119 · Cited by 26 · see citing works
“In the absence of a capacity for cell division, fibrosis becomes a mode of tissue repair and leads to tissue scarring (52, 53).”
BackgroundGeervliet, E., Terstappen, L. W. M. M., & Bansal, R. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115612 · Cited by 26 · see citing works
Centriole signaling restricts hepatocyte ploidy to maintain liver integrityPreprint
Sladky, V. C., Akbari, H., Tapias-Gomez, D., Evans, L. T., Drown, C. G., Strong, M. A., LoMastro, G. M., Larman, T. C., & Holland, A. (2022) · Genes & Development · doi:10.1101/gad.349727.122 · Cited by 22 · see citing works
Assessment of Drug-Induced Liver Injury through Cell Morphology and Gene Expression Analysis
Lejal, V., Cerisier, N., Rouquié, D., & Taboureau, O. (2023) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.2c00381 · Cited by 24 · see citing works
Effects of glyphosate exposure on western diet-induced non-alcoholic fatty liver disease in mice
Romualdo, G. R., Valente, L. C., dos Santos, A. C. S., Grandini, N. A., Corrêa, C. R., Vinken, M., Cogliati, B., Hou, D., & Barbisan, L. F. (2023) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2023.104286 · Cited by 16 · see citing works
Gao, L., Zuo, X., Dong, L.-L., Zhou, S., Wang, Z., Duan, Y., Chen, M., Zhu, Q., & Zhang, J. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.116317 · Cited by 16 · see citing works
Targeting ketone body metabolism to treat fatty liver disease
Kwon, S., Jeyaratnam, R., & Kim, K.-H. (2024) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.3389/jpps.2024.13375 · Cited by 17 · see citing works
Wijaya, L. S., Gábor, A., Pot, I., van de Have, L., Sáez-Rodríguez, J., Stevens, J. L., Dévédec, S. E. L., Callegaro, G., & van de Water, B. (2023) · Toxicological Sciences · doi:10.1093/toxsci/kfad121 · Cited by 17 · see citing works
Polyploidization of Hepatocytes: Insights into the Pathogenesis of Liver Diseases
Kim, J., Choi, H., Kim, H., Jee, Y., Noh, M., & Lee, M. (2022) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2022.070 · Cited by 12 · see citing works
Self-citationSsu72 Dual-Specific Protein Phosphatase: From Gene to Diseases
Hwang, S.-H., Kim, M.-H., & Lee, C.-W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073791 · Cited by 12 · see citing works
Patil, V. S., Harish, D. R., Sampat, G. H., Roy, S., Jalalpure, S., Khanal, P., Gujarathi, S. S., & Hegde, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311146 · Cited by 12 · see citing works
Fat storage-inducing transmembrane proteins: beyond mediating lipid droplet formation
Wang, G., Chen, A., Wu, Y. N., Wang, D., Chang, C., & Yu, G. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00391-z · Cited by 9 · see citing works
Oh, K., Choi, I., Gupta, H., Ganesan, R., Sharma, S. P., Won, S., Jeong, J., Lee, S.-B., Cha, M., Kwon, G.-H., et al. (2022) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2022.2155661 · Cited by 9 · see citing works
Chemical Switching: A Concept Inspired by Strategies from Biocatalysis and Organocatalysis
Visnes, T., Zhou, K., Kemas, A. M., Campopiano, D. J., Lauschke, V. M., & Michel, M. (2025) · ChemBioChem · doi:10.1002/cbic.202500220 · Cited by 9 · see citing works
Genetic and Cellular Contributions to Liver RegenerationPreprint
Liang, R. J., Lin, Y.-H., & Zhu, H. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a040832 · Cited by 8 · see citing works
Epithelial mechanics are maintained by inhibiting cell fusion with age in Drosophila
Dehn, A. S., Duhaime, L. G., Gogna, N., Nishina, P. M., Kelley, K., & Losick, V. P. (2023) · Journal of Cell Science · doi:10.1242/jcs.260974 · Cited by 7 · see citing works
Kim, J., Yang, I. S., Kim, H., Yoon, J.-Y., Han, Y., Seong, J. K., & Lee, M. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00309.2021 · Cited by 7 · see citing works
DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma
Smith, M. A., Alsten, S. C. V., Walens, A., Damrauer, J. S., Maduekwe, U. N., Broaddus, R. R., Love, M. I., Troester, M. A., & Hoadley, K. A. (2022) · Cancers · doi:10.3390/cancers14174282 · Cited by 6 · see citing works
Zhang, Y., Li, R., Li, H., Huang, Y., Mei, Y., Zheng, Y., Guo, Y., Zhou, Z., Yong, Z., Zhao, Y., et al. (2024) · Marine Biotechnology · doi:10.1007/s10126-024-10366-0 · Cited by 5 · see citing works
Hepatocyte integrity depends on c-Jun-controlled proliferation in Schistosoma mansoni infected mice
Härle, L., von Bülow, V., Knedla, L., Stettler, F., Müller, H., Zahner, D., Haeberlein, S., Windhorst, A., Tschuschner, A., Burg‐Roderfeld, M., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-47646-z · Cited by 5 · see citing works
Kirsch, G., Araujo, R. M. G., Melo, M. S., Nazari, E. M., & Figueiredo, B. R. S. (2025) · Chemosphere · doi:10.1016/j.chemosphere.2025.144756 · Cited by 4 · see citing works
Deng, H., Taishi, Y., Wang, G., Kong, Y., Zhang, R., & Zheng, X. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.117566 · Cited by 4 · see citing works
Hicks, J. A., Pike, B., & Liu, H. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.1020870 · Cited by 4 · see citing works
Riechelmann-Casarin, L., Valente, L. C., Otton, R., Barbisan, L. F., & Romualdo, G. R. (2025) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2025.104705 · Cited by 3 · see citing works
Assessment of Hepatocyte Ploidy by Flow Cytometry
Jin, Y., Anbarchian, T., & Nusse, R. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2557-6_12 · Cited by 3 · see citing works
Kang, X., Chen, H., Zhou, Z., Tu, S., Cui, B., Li, Y., Dong, S., Zhang, Q., & Xu, Y. (2023) · Advanced Biology · doi:10.1002/adbi.202300403 · Cited by 2 · see citing works
Dehn, A. S., Gogna, N., Nishina, P., & Losick, V. P. (2021) · bioRxiv · doi:10.1101/2021.08.09.455651 · Cited by 1 · see citing works
Ning, M., Song, L., Niu, X., Wang, Y., Liu, W., Hu, J., Cai, H., Song, W., Liu, L., Li, H., et al. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.132452 · Cited by 1 · see citing works
Hepatotoxic Potential of Doxorubicin in Albino Rats
Shami, A., Baloch, M. B., Khalid, A. M., Farzana, F., Nasim, M., & Ather, M. M. (2022) · Pakistan Journal of Medical and Health Sciences · doi:10.53350/pjmhs22161230
Yu, O. L., Zhou, Y., Lim, C. W., & CHING, Y. P. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4635430
Umar, J., Turhadi, T., Wihastuti, T. A., Fahmi, M., & Fatchiyah, F. (2025) · CyTA - Journal of Food · doi:10.1080/19476337.2025.2604377
Bukkuri, A., McLaughlin, J., Duncan, A. W., & Stallaert, W. (2026) · Evolution Medicine and Public Health · doi:10.1093/emph/eoag002
Effect of Kratom (Mitragyna speciosa) Hydrogel on Liver Function in Diabetic Burn Injury
Pramesti, R. A., Jazuli, M. A. S., Ismail, Z. H. W., Rihhadatulays, K. N. J., Hanafi, E. S. A. F., Jinan, P. R., Salim, H. M., & Bermawi, B. (2026) · International Islamic Medical Journal · doi:10.33086/iimj.v7i2.8239
Yang, M. J., Lyu, T., & Zhang, C. (2026) · The Journal of Precision Medicine Health and Disease · doi:10.1016/j.premed.2026.100052
- Authors
- Dewhurst, M. R., Ow, J. R., Zafer, G., van Hul, N. K. M., Wollmann, H., Bisteau, X., Brough, D., Choi, H., & Kaldis, P.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Manchester Academic Health Science Centre (GB)
- Corresponding author
- Kaldis, Philipp
- ORCID
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2020-11-04
- Volume
- 16
- Issue
- 11
- Pages
- e1009084
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC7641358
- OpenAlex
- W3082824354
- Cited by
- 42
- References
- 89
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 11 · 2022: 10 · 2021: 8 · 2020: 1
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lund University Publications (Lund University) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Research Foundation
- Agency for Science, Technology and Research
- National Research Foundation Singapore (NRF2016, NRF2016-CRP001-103)
- Stiftelsen för Strategisk Forskning (2009-1039, Dnr 2009-1039, Dnr IRC15‐0067, IRC15-0067)
- Lunds Universitet (2009-1039, IRC15-0067)
- Vetenskapsrådet (2009-1039, IRC15-0067, Dnr2009‐1039, Dnr IRC15-0067)
- Medical Research Council
- National Medical Research Council (NMRC/CBRG/0091/2015, CBRG/0091/2015)
- Medicinska Fakulteten, Lunds Universitet
- Institute of Molecular and Cell Biology
- Biomedical Research Council (1231AFG031)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- liver regeneration, liver fibrosis, liver inflammation, CDK2, polyploidy, DNA re-replication, p53 pathway, DNA damage, monocytes, cytokines, hepatocyte cell cycle
- MeSH terms
- Animals, Cell Cycle, Cell Division, Disease Models, Animal, Fibrosis, Hepatitis, Inflammation, Liver, Liver Cirrhosis, Male, Signal Transduction, CDC2 Protein Kinase, Cytokines, Apoptosis, Mice, Knockout, Hepatocytes, Cyclin-Dependent Kinase 2, Mice
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