Broad Distribution of Hepatocyte Proliferation in Liver Homeostasis and Regeneration
Open accessAbstract
Hepatocyte proliferation is the principal mechanism for generating new hepatocytes in liver homeostasis and regeneration. Recent studies have suggested that this ability is not equally distributed among hepatocytes but concentrated in a small subset of hepatocytes acting like stem cells, located around the central vein or distributed throughout the liver lobule and exhibiting active WNT signaling or high telomerase activity, respectively. These findings were obtained by utilizing components of these growth regulators as markers for genetic lineage tracing. Here, we used random lineage tracing to localize and quantify clonal expansion of hepatocytes in normal and injured liver. We found that modest proliferation of hepatocytes distributed throughout the lobule maintains the hepatocyte mass and that most hepatocytes proliferate to regenerate it, with diploidy providing a growth advantage over polyploidy. These results show that the ability to proliferate is broadly distributed among hepatocytes rather than limited to a rare stem cell-like population.
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Hepatocytes do not proliferate equally over time, as results obtained via three independent experimental approaches have led to the same conclusion, namely that zone 2 hepatocytes proliferate more than hepatocytes from the other zones.
“Nevertheless, hepatocytes do not proliferate equally over time, as results obtained via three independent experimental approaches have led to the same conclusion, namely that zone 2 hepatocytes proliferate more than hepatocytes from the other zones.75,86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
The Discussion (page unavailable) reports proliferation throughout the normal liver lobule, with a slight predominance in the midlobular zone, supporting the zone 2 comparison in that setting. It does not establish that three independent experimental approaches reached that conclusion, and the Results (page unavailable) report uniform proliferation across zones after repeated CCl4 injury. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInjury to zone 1 by allyl alcohol injection or DDC diet was compensated by proliferation of hepatocytes in zones 2 and 3.
“Additionally, injury to zone 1 by allyl alcohol injection or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet was compensated by proliferation of hepatocytes in zones 2 and 3.85,86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
The Results report that allyl alcohol caused periportal injury and that hepatocytes both adjacent to and farther from the injury proliferated. This supports the allyl-alcohol portion, but the cited paper does not report DDC-diet injury or explicitly identify the compensating hepatocytes as being in both zones 2 and 3. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRecent studies have demonstrated that hepatocytes are primarily maintained by the proliferation of pre-existing hepatocytes during liver homeostasis and regeneration.
“recent studies have demonstrated that hepatocytes are primarily maintained by the proliferation of pre-existing hepatocytes during liver homeostasis and regeneration14–19”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [14]
During homeostasis, zone 2 hepatocytes rather than a defined subpopulation seem to have increased proliferative potential.
“During homeostasis, zone 2 hepatocytes rather than a defined subpopulation seem to have increased proliferative potential.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
Hepatocyte renewal is not driven by zone 3, no hepatocytes formed particularly large clones, and hepatocyte proliferation was distributed throughout the lobule with larger hepatocyte clones more frequently found in zone 2.
“3D imaging of labelled cells and their progeny showed that hepatocyte renewal is not driven by zone 3, no hepatocytes formed particularly large clones, and hepatocyte proliferation was distributed throughout the lobule with larger hepatocyte clones more frequently found in zone 2.88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
Zone 2 hepatocytes labelled by AAV8-TBG-Cre or CreERT2 expressed from the Hamp2 or Mup3 promoters proliferated and clonally expanded.
“Zone 2 hepatocytes labelled by AAV8-TBG-Cre or CreERT2 expressed from the Hamp2 or Mup3 promoters also proliferated and clonally expanded.86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
Approximately 80% of hepatocytes randomly labelled by AAV8-TBG-Cre gave rise to expanding hepatocyte clones in mouse livers subjected to repeated CCl4 injury, indicating that proliferative hepatocytes are relatively abundant.
“However, ∼80% of hepatocytes randomly labelled by AAV8-TBG-Cre gave rise to expanding hepatocyte clones in mouse livers subjected to repeated CCl4 injury, indicating that proliferative hepatocytes are relatively abundant.88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [88]
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Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
Advanced CUBIC protocols for whole-brain and whole-body clearing and imaging
Susaki, E. A., Tainaka, K., Perrin, D., Yukinaga, H., Kuno, A., & Ueda, H. R. (2015) · Nature Protocols · doi:10.1038/nprot.2015.085 · Cited by 821 · 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
Coronary arteries form by developmental reprogramming of venous cells
Red‐Horse, K., Ueno, H., Weissman, I. L., & Krasnow, M. A. (2010) · Nature · doi:10.1038/nature08873 · Cited by 539 · see citing works
The ploidy conveyor of mature hepatocytes as a source of genetic variation
Duncan, A. W., Taylor, M. H., Hickey, R. D., Hanlon Newell, A. E., Lenzi, M. L., Olson, S. B., Finegold, M. J., & Grompe, M. (2010) · Nature · doi:10.1038/nature09414 · Cited by 525 · see citing works
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 · see citing works
Luche, H., Weber, O., Nageswara Rao, T., Blum, C., & Fehling, H. J. (2007) · European Journal of Immunology · doi:10.1002/eji.200636745 · Cited by 482 · see citing works
Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration
Miyaoka, Y., Ebato, K., Kato, H., Arakawa, S., Shimizu, S., & Miyajima, A. (2012) · Current Biology · doi:10.1016/j.cub.2012.05.016 · Cited by 461 · see citing works
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 · see citing works
Conditional telomerase induction causes proliferation of hair follicle stem cells
Sarin, K. Y., Cheung, P., Gilison, D., Lee, E., Tennen, R. I., Wang, E., Artandi, M. K., Oro, A. E., & Artandi, S. E. (2005) · Nature · doi:10.1038/nature03836 · Cited by 425 · see citing works
Susaki, E. A., & Ueda, H. R. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2015.11.009 · Cited by 297 · see citing works
De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation
Schaub, J. R., Huppert, K. A., Kurial, S. N. T., Hsu, B. Y., Cast, A. E., Donnelly, B., Karns, R. A., Chen, F., Rezvani, M., Luu, H. Y., et al. (2018) · Nature · doi:10.1038/s41586-018-0075-5 · Cited by 289 · see citing works
Self-citationWnt Proteins Promote Bone Regeneration
Minear, S. C., Leucht, P., Jiang, J., Liu, B., Zeng, A., Fuerer, C., Nusse, R., & Helms, J. A. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000231 · Cited by 266 · see citing works
Davidoff, A. M., Ng, C. Y. C., Zhou, J., Spence, Y., & Nathwani, A. C. (2003) · Blood · doi:10.1182/blood-2002-09-2889 · Cited by 244 · see citing works
Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury
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
Age mosaicism across multiple scales in adult tissues
Arrojo e Drigo, R., Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., Phan, S., Orphan, V., Lechene, C., Ellisman, M. H., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.010 · Cited by 137 · see citing works
A multifunctional reporter mouse line for Cre‐ and FLP‐dependent lineage analysis
Yamamoto, M., Shook, N. A., Kanisicak, O., Yamamoto, S., Wosczyna, M. N., Camp, J. R., & Goldhamer, D. J. (2009) · genesis · doi:10.1002/dvg.20474 · Cited by 136 · see citing works
The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice
Wilkinson, P. D., Delgado, E. R., Alencastro, F., Leek, M. P., Roy, N., Weirich, M. P., Stahl, E. C., Otero, P. A., Chen, M. I., Brown, W. K., et al. (2019) · Hepatology · doi:10.1002/hep.30286 · Cited by 135 · see citing works
Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates
Bell, P. L., Wang, L., Gao, G., Haskins, M. E., Tarantal, A. F., McCarter, R., Zhu, Y., Yu, H., & Wilson, J. M. (2011) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2011.06.002 · Cited by 71 · see citing works
Alvarado, T. F., Puliga, E., Preziosi, M., Poddar, M., Singh, S., Columbano, A., Nejak‐Bowen, K. N., & Monga, S. P. (2016) · Gene Expression · doi:10.3727/105221616x691631 · Cited by 47 · see citing works
Greig, J. A., Nordin, J. M. L., Draper, C., McMenamin, D., Chroscinski, E. A., Bell, P. L., Gray, J. T., Richman, L. K., & Wilson, J. M. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.07.008 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
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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
Kumar, S., Duan, Q., Wu, R., Harris, E. N., & Su, Q. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113869 · Cited by 355 · see citing works
Liver regeneration and inflammation: from fundamental science to clinical applications
Campana, L., Esser, H., Huch, M., & Forbes, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00373-7 · Cited by 307 · 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
Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair
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
Tumor cell plasticity in targeted therapy-induced resistance: Mechanisms and new strategies
Shi, Z.-D., Pang, K., Wu, Z.-X., Dong, Y., Hao, L., Qin, J.-X., Wang, W., Chen, Z.-S., & Han, C.-H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01383-x · Cited by 256 · see citing works
Amino acid metabolism, transport and signalling in the liver revisited.
Paulusma, C., Lamers, W., Bröer, S., & van de Graaf, S. V. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115074 · Cited by 162 · see citing works
Paris, J., & Henderson, N. C. (2022) · Hepatology · doi:10.1002/hep.32408 · Cited by 167 · see citing works
Organoids to model liver disease
Nuciforo, S., & Heim, M. H. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2020.100198 · Cited by 164 · see citing works
Epithelial–mesenchymal transition in tissue repair and degeneration
Youssef, K. K., & Nieto, M. A. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00733-z · Cited by 162 · see citing works
Epithelial Plasticity during Liver Injury and Regeneration
Gadd, V. L., Aleksieva, N., & Forbes, S. J. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.08.016 · Cited by 142 · see citing works
Cell Plasticity in Liver Regeneration
Li, W., Li, L., & Hui, L. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.01.007 · Cited by 167 · see citing works
Multimodal decoding of human liver regeneration
Matchett, K. P., Wilson-Kanamori, J. R., Portman, J. R., Kapourani, C. A., Fercoq, F., May, S., Zajdel, E., Beltran, M., Sutherland, E. F., Mackey, J. B. G., et al. (2024) · Nature · doi:10.1038/s41586-024-07376-2 · Cited by 140 · see citing works
“This would fit the ANXA2 staining in the injury area with HNF4a-negative/presumably dead hepatocytes, as well as the abnormal morphology of ANXA2+ hepatocytes.”
Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma
Garrido, A., & Djouder, N. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.08.005 · Cited by 122 · see citing works
Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology
Martini, T., Naef, F., & Tchorz, J. S. (2023) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031521-024831 · Cited by 113 · see citing works
Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis
Zhu, C., Tabas, I., Schwabe, R. F., & Pajvani, U. B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00365-6 · Cited by 112 · see citing works
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Chembazhi, U. V., Bangru, S., Hernaez, M., & Kalsotra, A. (2021) · Genome Research · doi:10.1101/gr.267013.120 · Cited by 102 · see citing works
A strategy of vascular‐targeted therapy for liver fibrosis
Yuan, L., Dong, M., Liu, Z., Xu, M., Huang, Z., Liu, H., Gao, Y., & Zhou, W. (2021) · Hepatology · doi:10.1002/hep.32299 · Cited by 100 · see citing works
Ma, R., Martínez-Ramírez, A. S., Borders, T. L., Gao, F., & Sosa-Pineda, B. (2020) · eLife · doi:10.7554/elife.46206 · Cited by 97 · see citing works
Zhang, L., Ma, X.-J.-N., Fei, Y.-Y., Han, H., Xu, J., Cheng, L., & Li, X. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108004 · Cited by 93 · see citing works
Hallmarks of stemness in mammalian tissues
Beumer, J., & Clevers, H. C. (2024) · Cell stem cell · doi:10.1016/j.stem.2023.12.006 · Cited by 91 · see citing works
ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation
Sun, T., Annunziato, S., Bergling, S., Sheng, C., Orsini, V., Forcella, P., Pikiolek, M., Kancherla, V., Holwerda, S., Imanci, D., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.05.013 · Cited by 84 · see citing works
Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy
Richter, M. L., Deligiannis, I. K., Yin, K., Danese, A., Lleshi, E., Coupland, P., Vallejos, C. A., Matchett, K. P., Henderson, N. C., Colome-Tatche, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24543-5 · Cited by 75 · see citing works
Diploid hepatocytes drive physiological liver renewal in adult humans
Heinke, P., Rost, F., Rode, J., Trus, P., Simonova, I., Lázár, E., Feddema, J., Welsch, T., Alkass, K., Salehpour, M., et al. (2022) · Cell Systems · doi:10.1016/j.cels.2022.05.001 · Cited by 73 · see citing works
Paligenosis: Cellular Remodeling During Tissue Repair
Brown, J. W., Cho, C. J., & Mills, J. C. (2021) · Annual Review of Physiology · doi:10.1146/annurev-physiol-061121-035954 · Cited by 71 · see citing works
Harnessing reactive oxygen/nitrogen species and inflammation: Nanodrugs for liver injury
Liu, M., Huang, Q., Zhu, Y., Chen, L., Li, Y., Gong, Z., & Ai, K. (2022) · Materials Today Bio · doi:10.1016/j.mtbio.2022.100215 · Cited by 69 · see citing works
Liver regeneration: Cellular origin and molecular mechanisms
Huang, R. C. C., Zhang, X., Gracia‐Sancho, J., & Xie, W. (2022) · Liver International · doi:10.1111/liv.15174 · Cited by 68 · see citing works
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Vandel, J., Dubois‐Chevalier, J., Gheeraert, C., Derudas, B., Raverdy, V., Thuillier, D., Gaal, L., Francque, S., Pattou, F., Staels, B., et al. (2021) · Hepatology · doi:10.1002/hep.31312 · Cited by 61 · see citing works
Zhou, L., Yu, K. H., Wong, T. L., Zhang, Z., Chan, C. H., Loong, J. H. C., Che, N., Yu, H., Tan, K. V., Tong, M., et al. (2021) · Gut · doi:10.1136/gutjnl-2021-324321 · Cited by 63 · see citing works
Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis
Overi, D., Carpino, G., Franchitto, A., Onori, P., & Gaudio, E. (2020) · Cells · doi:10.3390/cells9030590 · Cited by 61 · see citing works
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Peng, W. C., Kraaier, L. J., & Kluiver, T. A. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00579-x · Cited by 59 · see citing works
Shiota, J., Samuelson, L. C., & Razumilava, N. (2021) · Hepatology · doi:10.1002/hep.31772 · Cited by 57 · see citing works
VEGF‐FGF Signaling Activates Quiescent CD63+ Liver Stem Cells to Proliferate and Differentiate
Chen, F., Zhang, K., Wang, M., He, Z., Yu, B., Wang, X., Pan, X., Luo, Y., Xu, S., Lau, J. T. Y., et al. (2024) · Advanced Science · doi:10.1002/advs.202308711 · Cited by 57 · see citing works
Self-citationJin, Y., Zhang, J., Xu, Y., Yi, K., Li, F., Zhou, H., Wang, H., Chan, H. F., Lao, Y.-H., Lv, S., et al. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.05.001 · Cited by 55 · see citing works
Progress in human liver organoids
Sun, L., & Hui, L. (2020) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjaa013 · Cited by 55 · see citing works
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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
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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
Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver
Lin, H., Huang, Y.-S., Fustin, J., Doi, M., Chen, H.-T., Lai, H.-H., Lin, S.-H., Lee, Y.-L., King, P.-C., Hou, H.-S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20572-8 · Cited by 46 · see citing works
Liver macrophages: development, dynamics, and functions
Nusse, Y., & Kubes, P. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01298-3 · Cited by 50 · 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
Mason, W. S., Jilbert, A. R., & Litwin, S. (2021) · Viruses · doi:10.3390/v13020210 · Cited by 47 · see citing works
Wnt/β-Catenin signaling pathway in hepatocellular carcinoma: pathogenic role and therapeutic target
Zhao, Z., Cui, T., Wei, F., Zhou, Z., Sun, Y., Gao, C., Xu, X., & Zhang, H. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1367364 · Cited by 45 · see citing works
The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease
Annunziato, S., Sun, T., & Tchorz, J. S. (2022) · Hepatology · doi:10.1002/hep.32328 · Cited by 45 · see citing works
Trinh, V. Q.-H., Lee, T.-F., Lemoinne, S., Ray, K. C., Ybanez, M. D., Tsuchida, T., Carter, J. K., Agudo, J., Brown, B. D., Akat, K. M., et al. (2023) · Science Signaling · doi:10.1126/scisignal.adf6696 · Cited by 45 · see citing works
An Emerging Frontier in Intercellular Communication: Extracellular Vesicles in Regeneration
Avalos, P. N., & Forsthoefel, D. J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.849905 · Cited by 49 · see citing works
The Role of Liver Zonation in Physiology, Regeneration, and Disease
Panday, R., Monckton, C. P., & Khetani, S. R. (2022) · Seminars in Liver Disease · doi:10.1055/s-0041-1742279 · Cited by 44 · 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
Cellular origins of regenerating liver and hepatocellular carcinoma
Holczbauer, Á., Wangensteen, K. J., & Shin, S. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100416 · Cited by 39 · see citing works
Wild, S. L., Elghajiji, A., Rodriguez, C. G., Weston, S. D., Burke, Z. D., & Tosh, D. (2020) · Genes · doi:10.3390/genes11101163 · Cited by 39 · see citing works
Mak, K. M., & Shin, D. W. (2020) · The Anatomical Record · doi:10.1002/ar.24560 · Cited by 35 · see citing works
Lin, Y.-H., Wei, Y., Zeng, Q., Wang, Y., Pagani, C. A., Li, L., Zhu, M., Wang, Z., Hsieh, M.-H., Corbitt, N., et al. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.04.007 · Cited by 33 · see citing works
Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis
Kurosaki, S., Nakagawa, H., Hayata, Y., Kawamura, S., Matsushita, Y., Yamada, T., Uchino, K., Hayakawa, Y., Suzuki, N., Hata, M., et al. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100315 · Cited by 34 · see citing works
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Zhang, Y., Zeng, F., Han, X., Weng, J., & Gao, Y. (2020) · Stem cell research & therapeutics · doi:10.1186/s13287-020-01941-y · Cited by 24 · see citing works
Delgado‐Coello, B. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e06449 · Cited by 31 · 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
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Lu, T., Park, S., Zhu, J. J., Wang, Y., Zhan, X., Wang, X., Wang, L., Zhu, H., & Wang, T. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108589 · Cited by 26 · see citing works
Epigenetic Regulation of Cell-Fate Changes That Determine Adult Liver Regeneration After Injury
Aloia, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.643055 · Cited by 25 · see citing works
Li, Y., Ge, L., Chen, X., Mao, Y., Gu, X., Ren, B., Zeng, Y., Chen, M., Chen, S., Liu, J., et al. (2021) · npj Regenerative Medicine · doi:10.1038/s41536-021-00126-2 · Cited by 25 · see citing works
Cell transplantation-based regenerative medicine in liver diseases
Cardinale, V., Lanthier, N., Baptista, P. M., Carpino, G., Carnevale, G., Orlando, G., Angelico, R., Manzia, T. M., Schuppan, D., Pinzani, M., et al. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.06.005 · Cited by 26 · see citing works
Li, F., Song, G., Wang, X., Sun, Y., Zhou, S., Zhang, Y., Hua, J., Zhu, B., Yang, L., Zhang, W., et al. (2023) · Environmental Science & Technology · doi:10.1021/acs.est.3c06747 · Cited by 25 · see citing works
Ruz‐Maldonado, I., González, J. T., Zhang, H., Sun, J., Bort, A., Kabir, I., Kibbey, R. G., Suárez, Y., Greif, D. M., & Fernandez-Hernando, C. F. (2024) · Nature Communications · doi:10.1038/s41467-024-45439-0 · Cited by 26 · see citing works
The origin of hepatocellular carcinoma depends on metabolic zonation
Guo, J., Liang, R., Chung, A., Li, Z., Li, B., Chen, E., Li, L., Wang, J., Hsieh, M.-H., Fang, I. X., et al. (2026) · Science · doi:10.1126/science.adv7129 · Cited by 24 · see citing works
Pek, N. M. Q., Liu, K. J., Nichane, M., & Ang, L. T. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.016 · Cited by 25 · see citing works
Cell and Tissue Therapy for the Treatment of Chronic Liver Disease
Bram, Y., Nguyen, D.-H. T., Gupta, V., Park, J., Richardson, C., Chandar, V., & Schwartz, R. E. (2021) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-112619-044026 · Cited by 24 · 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
In the zone for liver proliferation
Andersson, E. R. (2021) · Science · doi:10.1126/science.abg4864 · Cited by 23 · see citing works
Decoding liver fibrogenesis with single-cell technologies
Zhou, T., Musunuru, K., Lui, K. O., & Ding, Q. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac040 · Cited by 21 · see citing works
Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications
Jiang, M., Ren, J., Belmonte, J. C. I., & Liu, G. (2023) · FEBS Journal · doi:10.1111/febs.16930 · Cited by 20 · see citing works
All routes lead to Rome: multifaceted origin of hepatocytes during liver regeneration
Gao, C., & Peng, J. (2021) · Cell Regeneration · doi:10.1186/s13619-020-00063-3 · Cited by 21 · see citing works
Miura, A., Hosono, T., & Seki, T. (2021) · Scientific Reports · doi:10.1038/s41598-021-88989-9 · Cited by 21 · see citing works
Hepatic Regeneration in Cirrhosis
Jindal, A., Jagdish, R. K., & Kumar, A. (2021) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2021.08.029 · Cited by 20 · see citing works
Multiple Facets of Cellular Homeostasis and Regeneration of the Mammalian Liver
Huppert, S. S., & Schwartz, R. E. (2022) · Annual Review of Physiology · doi:10.1146/annurev-physiol-032822-094134 · Cited by 19 · see citing works
A latent Axin2+/Scx+ progenitor pool is the central organizer of tendon healing
Grinstein, M., Tsai, S. L., Montoro, D. T., Freedman, B. R., Dingwall, H. L., Villaseñor, S., Zou, K., Sade-Feldman, M., Tanaka, M. J., Mooney, D. J., et al. (2024) · npj Regenerative Medicine · doi:10.1038/s41536-024-00370-2 · Cited by 21 · 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
Peng, J., Li, F., Wang, J., Wang, C., Jiang, Y., Liu, B., He, J., Yuan, K., Pan, C., Lin, M., et al. (2022) · Cell Discovery · doi:10.1038/s41421-022-00474-3 · Cited by 17 · see citing works
ScRNA-seq and ST-seq in liver research
He, J., Deng, C., Krall, L., & Shan, Z. (2023) · Cell Regeneration · doi:10.1186/s13619-022-00152-5 · Cited by 17 · see citing works
Cell atlas of CCl4-induced progressive liver fibrosis reveals stage-specific responses
Guo, P.-C., 吉林大学动物医学学院人兽共患病研究所人兽共患病研究教育部重点实验室, 人., Zuo, J., Huang, K.-K., Lai, G., Zhang, X., An, J., Li, J., Li, L., Wu, L. L., et al. (2023) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2023.031 · Cited by 17 · see citing works
Regulation of chromatin organization during animal regeneration
Jia, X., Lin, W., & Wang, W. (2023) · Cell Regeneration · doi:10.1186/s13619-023-00162-x · Cited by 17 · see citing works
Bao, Z., Guo, C., Chen, Y., Li, C., Lei, T., Zhou, S., Qi, D., & Xiang, Z. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112718 · Cited by 17 · see citing works
Compartmentalization, cooperation, and communication: The 3Cs of Hepatocyte zonation
Porat‐Shliom, N. (2023) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2023.102292 · Cited by 16 · see citing works
Relationships Between Regeneration, Wound Healing, and Cancer
Maggiore, G., & Zhu, H. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062822-123558 · Cited by 16 · see citing works
Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases
Safarikia, S., Carpino, G., Overi, D., Cardinale, V., Venere, R., Franchitto, A., Onori, P., Alvaro, D., & Gaudio, E. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00479 · Cited by 16 · see citing works
Contributions of biliary epithelial cells to hepatocyte homeostasis and regeneration in zebrafish
Zhang, W., Chen, J., Ni, R., Yang, Q., Luo, L., & He, J. (2021) · iScience · doi:10.1016/j.isci.2021.102142 · Cited by 15 · see citing works
Tissue regeneration: Unraveling strategies for resolving pathological fibrosis
Li, J., Wang, S., Yuan, J., Mao, X., Wang, X., Zhang, L., Dong, Q., Chen, Z., Wang, Y., & Tang, N. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.10.002 · Cited by 16 · see citing works
Spatial-temporal proliferation of hepatocytes during pregnancy revealed by genetic lineage tracing
He, S., Guo, Z., Zhou, M., Wang, H., Zhang, Z., Shi, M., Li, X., Yang, X., & He, L. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.09.002 · Cited by 15 · see citing works
Microscale tissue engineering of liver lobule models: advancements and applications
Wang, Q., Liu, J., Yin, W., Wang, A., Zheng, J., Wang, Y., & Dong, J. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1303053 · Cited by 15 · see citing works
Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase
Darmasaputra, G. S., Geerlings, C. C., Lopes, S. M. C. D. S., Clevers, H., & Galli, M. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202403020 · Cited by 12 · see citing works
Kim, K., & Lee, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23010566 · Cited by 14 · see citing works
Bio inspired heuristic computing scheme for the human liver nonlinear model
Sabir, Z., Saïd, S. B., & Al‐Mdallal, Q. M. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28912 · Cited by 14 · see citing works
Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation
Koopmans, T., & van Rooij, E. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01145-y · Cited by 14 · see citing works
Epigenetic Signatures and Plasticity of Intestinal and Other Stem Cells
Saxena, M., & Shivdasani, R. A. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034520 · Cited by 13 · see citing works
Sato, Y., Yoneda, A., Shimizu, F., Nishimura, M., Shimoyama, R., Tashiro, Y., Kurata, W., & Niitsu, Y. (2021) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15587 · Cited by 13 · see citing works
Wiszniewski, G., Jarmołowicz, S., hassaan, M. S., Kamaszewski, M., Szudrowicz, H., Terech-Majewska, E., Kawalski, K., Martynow, J., Szczepański, A., & Siwicki, A. K. (2022) · Aquaculture Reports · doi:10.1016/j.aqrep.2022.101196 · Cited by 13 · see citing works
Jiang, M., Guo, R., Ai, Y., Wang, G., Tang, P., Jia, X., He, B., Yuan, Q., & Xie, X. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100670 · Cited by 13 · see citing works
Passman, A. M., Haughey, M. J., Carlotti, E., Williams, M. J., Cereser, B., Lin, M., Devkumar, S., Gabriel, J. P., Gringeri, E., Cillo, U., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.03.044 · Cited by 12 · see citing works
Li, Y., Li, M., Duan, S., Zhang, S., Lu, H., Guo, X., & Zhong, K. (2024) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2024.116817 · Cited by 13 · see citing works
- Authors
- Chen, F., Jimenez, R. J., Sharma, K., Luu, H. Y., Hsu, B. Y., Ravindranathan, A., Stohr, B. A., & Willenbring, H.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Chen, Feng
- Willenbring, Holger
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 26
- Issue
- 1
- Pages
- 27-33.e4
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC8009755
- OpenAlex
- W2996029077
- Cited by
- 236
- References
- 21
- Citations by year
- 2026: 15 · 2025: 32 · 2024: 34 · 2023: 51 · 2022: 34 · 2021: 44 · 2020: 26
- FWCI
- 16.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Eli and Edythe Broad Foundation (R01 AA026578, CIRM DISC2-10088)
- California Institute of Regenerative Medicine
- National Institutes of Health (P30 DK026743, R01 AA026578, T32 DK060414)
- Novartis
- Jane Coffin Childs Memorial Fund for Medical Research
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- hepatocyte proliferation, liver homeostasis, liver regeneration, clonal expansion, Wnt signaling, telomerase, polyploidy, diploidy, liver lobule
- MeSH terms
- Homeostasis, Liver, Liver Regeneration, Hepatocytes, Cell Proliferation
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