Cited by 533Liver physiology and pathologyTissue Engineering and Regenerative MedicineDrug-Induced Hepatotoxicity and Protection

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

Open access

Raven, Alexander, Lu, Wei-Yu, Man, Tak Yung, Ferreira-Gonzalez, Sofia, O’Duibhir, Eoghan, Dwyer, Benjamin J., Thomson, John P., Meehan, Richard R., Bogorad, Roman, Koteliansky, Victor, Kotelevtsev, Yuri, ffrench-Constant, Charles, Boulter, Luke, Forbes, Stuart J.·2017·Nature

DOI 10.1038/nature23015PMC PMC5522613

Open this paper in CoChat — free account Open PDF

Abstract

After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired-a feature of human chronic liver disease. It is unclear whether other liver cell types can regenerate hepatocytes. Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of β1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-integrin knockdown or p21 overexpression, resulting in the significant emergence of cholangiocyte-derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/nature23015

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
Globally optimal stitching of tiled 3D microscopic image acquisitions
Preibisch, S., Saalfeld, S., & Tomancak, P. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp184 · Cited by 2,452
In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
Huch, M., Dorrell, C., Boj, S. F., van Es, J. H., Li, V. S. W., van de Wetering, M., Sato, T., Hamer, K., Sasaki, N., Finegold, M. J., et al. (2013) · Nature · doi:10.1038/nature11826 · Cited by 1,555
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
A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice
Mitchell, C., & Willenbring, H. (2008) · Nature Protocols · doi:10.1038/nprot.2008.80 · Cited by 577
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
Robust cellular reprogramming occurs spontaneously during liver regeneration
Yanger, K., Zong, Y., Maggs, L. R., Shapira, S. N., Maddipati, R., Aiello, N. M., Thung, S. N., Wells, R. G., Greenbaum, L. E., & Stanger, B. Z. (2013) · Genes & Development · doi:10.1101/gad.207803.112 · Cited by 484
Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction
Richardson, M. M., Jonsson, J. R., Powell, E. E., Brunt, E. M., Neuschwander–Tetri, B. A., Bhathal, P. S., Dixon, J. B., Weltman, M. D., Tilg, H., Moschen, A. R., et al. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.05.012 · Cited by 482
Hepatic progenitor cells of biliary origin with liver repopulation capacity
Lu, W.-Y., Bird, T. G., Boulter, L., Tsuchiya, A., Cole, A. M., Hay, T., Guest, R. V., Wojtacha, D., Man, T. Y., Mackinnon, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3203 · Cited by 479
Self-citation
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

Show all 30 references

Sorted by citations

Cholangiocarcinoma 2020: the next horizon in mechanisms and management
Banales, J. M., Marin, J. J. G., Lamarca, A., Rodrigues, P. M., Khan, S. A., Roberts, L. R., Cardinale, V., Carpino, G., Andersen, J. B., Braconi, C., et al. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0310-z · Cited by 2,411
Self-citation
A human liver cell atlas reveals heterogeneity and epithelial progenitors
Aizarani, N., Saviano, A., Sagar, Mailly, L., Durand, S., Herman, J. S., Pessaux, P., Baumert, T. F., & Grün, D. (2019) · Nature · doi:10.1038/s41586-019-1373-2 · Cited by 1,147
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
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
Supramolecular Adhesive Hydrogels for Tissue Engineering Applications
Zhao, Y., Song, S., Ren, X., Zhang, J., Lin, Q., & Zhao, Y. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00815 · Cited by 714
Cholangiocyte pathobiology
Banales, J. M., Huebert, R. C., Karlsen, T., Strazzabosco, M., LaRusso, N. F., & Gores, G. J. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0125-y · Cited by 517
Ductular reaction in liver diseases: pathological mechanisms and translational significances
Sato, K., Marzioni, M., Meng, F., Francis, H., Glaser, S., & Alpini, G. (2019) · Hepatology · doi:10.1002/hep.30150 · Cited by 423
Liver diseases: epidemiology, causes, trends and predictions
Gan, C., Yuan, Y., Shen, H., Gao, J., Kong, X., Che, Z., Guo, Y., Wang, H., Dong, E., & Xiao, J. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02072-z · Cited by 416
Liver organoids: from basic research to therapeutic applications
Prior, N., Inacio, P., & Huch, M. (2019) · Gut · doi:10.1136/gutjnl-2019-319256 · Cited by 356
Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids
Marsee, A., Roos, F. J. M., Verstegen, M. M. A., Marsee, A., Roos, F., Verstegen, M., Clevers, H., Vallier, L., Takebe, T., Huch, M., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.04.005 · Cited by 310
Self-citation
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
Self-citation
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
Chronic Liver Injury Induces Conversion of Biliary Epithelial Cells into Hepatocytes
Deng, X., Zhang, X., Li, W., Feng, R.-X., Li, L., Yi, G.-R., Zhang, X.-N., Yin, C., Yu, H.-Y., Zhang, J.-P., et al. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.05.022 · Cited by 289
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
Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases
Li, Y., Lui, K. O., & Zhou, B. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0023-y · Cited by 287
Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
Pepe-Mooney, B. J., Dill, M. T., Alemany, A., Ordovas-Montanes, J., Matsushita, Y., Rao, A., Sen, A., Miyazaki, M., Anakk, S., Dawson, P. A., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.04.004 · Cited by 266
TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence
Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261
“We have recently reported in an in vivo model of hepatocyte growth arrest that cholangiocytes, which expand as a ductular reaction, may act as facultative stem cells for generating hepatocytes with replacement of hepatocytes occurring over weeks to months (29).”
Self-citation
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
Comparative regenerative mechanisms across different mammalian tissues
Iismaa, S. E., Kaidonis, X., Nicks, A. M., Bogush, N., Kikuchi, K., Naqvi, N., Harvey, R. P., Husain, A., & Graham, R. M. (2018) · npj Regenerative Medicine · doi:10.1038/s41536-018-0044-5 · Cited by 270
Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis
Ramachandran, P., Matchett, K. P., Dobie, R., Wilson-Kanamori, J. R., & Henderson, N. C. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0304-x · Cited by 253
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
Defining Adult Stem Cells by Function, not by Phenotype
Clevers, H., & Watt, F. M. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062917-012341 · Cited by 245
The balancing act of the liver: tissue regeneration versus fibrosis
Cordero-Espinoza, L., & Huch, M. (2018) · Journal of Clinical Investigation · doi:10.1172/jci93562 · Cited by 233
YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury
Planas-Paz, L., Sun, T., Pikiolek, M., Cochran, N. R., Bergling, S., Orsini, V., Yang, Z., Sigoillot, F., Jetzer, J., Syed, M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.04.005 · Cited by 216
Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer
Zeng, Y., & Jin, R. U. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.12.004 · Cited by 221
Development of the liver: Insights into organ and tissue morphogenesis
Ober, E. A., & Lemaigre, F. P. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.01.005 · Cited by 222
Hippo signalling in the liver: role in development, regeneration and disease
Russell, J. O., & Camargo, F. D. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00571-w · Cited by 211
The landscape of gene mutations in cirrhosis and hepatocellular carcinoma
Müller, M., Bird, T. G., & Nault, J. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.019 · Cited by 182
Defining Adult Stem Cell Function at Its Simplest: The Ability to Replace Lost Cells through Mitosis
Post, Y., & Clevers, H. C. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.07.002 · Cited by 181
Understanding Liver Regeneration
Gilgenkrantz, H., & Collin de l'Hortet, A. (2018) · The American Journal of Pathology · doi:10.1016/j.ajpath.2018.03.008 · Cited by 171
Diverse mechanisms for endogenous regeneration and repair in mammalian organs
Wells, J. M., & Watt, F. M. (2018) · Nature · doi:10.1038/s41586-018-0073-7 · Cited by 169
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
Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens
Fu, G.-B., Huang, W.-J., Zeng, M., Zhou, X., Wu, H.-P., Liu, C.-C., Wu, H., Weng, J., Zhang, H.-D., Cai, Y.-C., et al. (2019) · Cell Research · doi:10.1038/s41422-018-0103-x · Cited by 167
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
Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns
Ko, S., Russell, J. O., Molina, L. M., & Monga, S. P. (2019) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032824 · Cited by 168
Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration
Aloia, L., McKie, M. A., Vernaz, G., Cordero-Espinoza, L., Aleksieva, N., van den Ameele, J., Antonica, F., Font-Cunill, B., Raven, A., Aiese Cigliano, R., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0402-6 · Cited by 160
Self-citation
Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells
Castelli, G., Pelosi, E., & Testa, U. (2017) · Cancers · doi:10.3390/cancers9090127 · Cited by 162
Single-cell atlas of human liver development reveals pathways directing hepatic cell fates
Wesley, B. T., Ross, A. D. B., Muraro, D., Miao, Z., Saxton, S., Tomaz, R. A., Morell, C. M., Ridley, K., Zacharis, E. D., Petrus-Reurer, S., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00989-7 · Cited by 146
Acquisition of epithelial plasticity in human chronic liver disease
Gribben, C., Galanakis, V., Calderwood, A., Williams, E. C., Chazarra-Gil, R., Larraz, M., Frau, C., Puengel, T., Guillot, A., Rouhani, F. J., et al. (2024) · Nature · doi:10.1038/s41586-024-07465-2 · Cited by 142
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
Self-citation
Cell therapy for advanced liver diseases: repair or rebuild
Dwyer, B. J., Macmillan, M. T., Brennan, P. N., & Forbes, S. J. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.09.014 · Cited by 141
Self-citation
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
“In addition, this Figure shows peak proliferation at the same time as peak necrosis.”
Modeling Human Digestive Diseases With CRISPR-Cas9–Modified Organoids
Fujii, M., Clevers, H. C., & Sato, T. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.11.048 · Cited by 146
Identifying specific functional roles for senescence across cell types
(2024) · doi:10.1016/j.cell.2024.09.021 · Cited by 139
Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer
Sáenz, J. B., & Mills, J. C. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2018.5 · Cited by 138
Bipotent transitional liver progenitor cells contribute to liver regeneration
Pu, W., Zhu, H., Zhang, M., Pikiolek, M., Ercan, C., Li, J., Huang, X., Han, X., Zhang, Z., Lv, Z., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01335-9 · Cited by 138
Hepatocyte‐Specific β‐Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes
Russell, J. O., Lu, W., Okabe, H., Abrams, M. T., Oertel, M., Poddar, M., Singh, S., Forbes, S. J., & Monga, S. P. (2018) · Hepatology · doi:10.1002/hep.30270 · Cited by 136
Self-citation
Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers
Li, L., Cui, L., Lin, P., Liu, Z., Bao, S., Ma, X., Nan, H., Zhu, W., Cen, J., Mao, Y., et al. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.01.009 · Cited by 134
Roles of mTOR Signaling in Tissue Regeneration
Wei, X., Luo, L., & Chen, J.-Z. (2019) · Cells · doi:10.3390/cells8091075 · Cited by 136
Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors
Segal, J. M., Kent, D., Wesche, D. J., Ng, S. S., Serra, M. P., Oulès, B., Kar, G., Emerton, G., Blackford, S. J. I., Darmanis, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11266-x · Cited by 128
PPARs in liver physiology
Berthier, A., Johanns, M., Zummo, F. P., Lefebvre, P., & Staels, B. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166097 · Cited by 125
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 123
The Roles of Notch Signaling in Liver Development and Disease
Adams, J., & Jafar‐Nejad, H. (2019) · Biomolecules · doi:10.3390/biom9100608 · Cited by 118
Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling
Torre, S. D. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.572490 · Cited by 125
Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity
Weng, P., Aure, M. H., Maruyama, T., & Ovitt, C. E. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.016 · Cited by 114
Epithelial Stem and Progenitor Cells in Lung Repair and Regeneration
Alysandratos, K., Herriges, M. J., & Kotton, D. N. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-041520-092904 · Cited by 119
Liver progenitor cell-driven liver regeneration
So, J., Kim, A. S., Lee, S., & Shin, D. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0483-0 · Cited by 117
Lineage Tracing Reveals the Bipotency of SOX9+ Hepatocytes during Liver Regeneration
Han, X., Wang, Y., Pu, W., Huang, X., Qiu, L., Li, Y., Yu, W., Zhao, H., Liu, X., He, L., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.01.010 · Cited by 113
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
Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury‐Induced Wnt/β‐Catenin Signaling
Zhao, L., Jin, Y., Donahue, K., Tsui, M., Fish, M., Logan, C. Y., Wang, B., & Nusse, R. (2019) · Hepatology · doi:10.1002/hep.30563 · Cited by 111
HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
Hernandez, C., Huebener, P., Pradere, J.-P., Antoine, D. J., Friedman, R. A., & Schwabe, R. F. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91786 · Cited by 110
Regional Differences in Human Biliary Tissues and Corresponding In Vitro–Derived Organoids
Rimland, C. A., Tilson, S. G., Morell, C. M., Tomaz, R. A., Lu, W., Adams, S. E., Georgakopoulos, N., Otaizo‐Carrasquero, F., Myers, T. G., Ferdinand, J. R., et al. (2021) · Hepatology · doi:10.1002/hep.31252 · Cited by 110
Self-citation
The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice
Ritschka, B., Knauer-Meyer, T., Gonçalves, D. S., Mas, A., Plassat, J.-L., Durik, M., Jacobs, H., Pedone, E., Di Vicino, U., Cosma, M. P., et al. (2020) · Genes & Development · doi:10.1101/gad.332643.119 · Cited by 105
HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
Khambu, B., Huda, N., Chen, X., Antoine, D. J., Li, Y., Dai, G., Köhler, U. A., Zong, W., Waguri, S., Werner, S., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91814 · Cited by 106
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
Lgr5 + pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis
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
Organism-wide, cell-type-specific secretome mapping of exercise training in mice
Wei, W., Riley, N. M., Lyu, X., Shen, X., Guo, J., Raun, S. H., Zhao, M., Moya-Garzón, M. D., Basu, H., Tung, A. S.-H., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.04.011 · Cited by 101
Hallmarks of regeneration
Poss, K. D., & Tanaka, E. M. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.07.007 · Cited by 97
The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip
Bonis, V., Rossell, C., & Gehart, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.661931 · Cited by 103
Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo
Tanimizu, N., Ichinohe, N., Sasaki, Y., Itoh, T., Sudo, R., Yamaguchi, T., Katsuda, T., Ninomiya, T., Tokino, T., Ochiya, T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23575-1 · Cited by 94
Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells
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 95
Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury
Manco, R., Clerbaux, L.-A., Verhulst, S., Bou Nader, M., Sempoux, C., Ambroise, J., Bearzatto, B., Gala, J. L., Horsmans, Y., van Grunsven, L., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.02.003 · Cited by 92
Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity But Develop Fewer Hepatocellular Carcinomas Following Chronic Liver Injury
Lin, Y.-H., Zhang, S., Zhu, M., Lu, T., Chen, K., Wen, Z., Wang, S., Xiao, G., Luo, D., Jia, Y., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.026 · Cited by 95
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 92
Ductular Reaction Cells Display an Inflammatory Profile and Recruit Neutrophils in Alcoholic Hepatitis
Aguilar‐Bravo, B., Rodrigo‐Torres, D., Ariño, S., Coll, M., Pose, E., Blaya, D., Graupera, I., Perea, L., Vallverdú, J., Rubio‐Tomás, T., et al. (2018) · Hepatology · doi:10.1002/hep.30472 · Cited by 90
Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology
Torre, S. D. (2021) · Cells · doi:10.3390/cells10092502 · Cited by 91
Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease
Verstegen, M. M. A., Roos, F. J. M., Burka, K., Gehart, H., Jager, M., de Wolf, M., Bijvelds, M. J. C., de Jonge, H. R., Ardisasmita, A. I., van Huizen, N. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-79082-8 · Cited by 86
Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration
Bangru, S., Arif, W., Seimetz, J., Bhate, A., Chen, J., Rashan, E. H., Carstens, R. P., Anakk, S., & Kalsotra, A. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0129-2 · Cited by 85
Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8
Ko, S., Russell, J. O., Tian, J., Gao, C., Kobayashi, M., Feng, R., Yuan, X., Shao, C., Ding, H., Poddar, M., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.09.039 · Cited by 87
Calcium Signaling in Liver Injury and Regeneration
Oliva‐Vilarnau, N., Hankeová, S., Vorrink, S. U., Mkrtchian, S., Andersson, E. R., & Lauschke, V. M. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00192 · Cited by 85
The evolving definition of salivary gland stem cells
Rocchi, C., Barazzuol, L., & Coppes, R. P. (2021) · npj Regenerative Medicine · doi:10.1038/s41536-020-00115-x · Cited by 86
Farnesoid X Receptor Activation Impairs Liver Progenitor Cell–Mediated Liver Regeneration via the PTEN‐PI3K‐AKT‐mTOR Axis in Zebrafish
Jung, K., Kim, M., So, J., Lee, S., Ko, S., & Shin, D. (2020) · Hepatology · doi:10.1002/hep.31679 · Cited by 80
Cell of origin in biliary tract cancers and clinical implications
Moeini, A., Haber, P. K., & Sia, D. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100226 · Cited by 85
Generation and Differentiation of Adult Tissue-Derived Human Thyroid Organoids
Ogundipe, V. M. L., Groen, A. H., Hosper, N. A., Nagle, P. W., Heß, J., Faber, H., Bruin, A. L. J.-D., Baanstra, M., Links, T. P., Unger, K., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.02.011 · Cited by 82
Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma
Tan, S., Zhao, J., Sun, Z., Cao, S., Niu, K., Zhong, Y., Wang, H., Shi, L., Pan, H., Hu, J., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2005353117 · Cited by 75
Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation
Cordero-Espinoza, L., Dowbaj, A. M., Kohler, T. N., Strauss, B., Sarlidou, O., Belenguer, G., Pacini, C., Martins, N. P., Dobie, R., Wilson-Kanamori, J. R., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.07.002 · Cited by 74
“In addition, severe tissue damage and hepatocyte senescence inducecellular plasticity in the ductal compartment and endow the otherwise unipotent cholangiocytes with the capacity to replace lost hepatocyte mass (Choi et al., 2014; Raven et al., 2017).”
Background
Mouth-Watering Results: Clinical Need, Current Approaches, and Future Directions for Salivary Gland Regeneration
Rocchi, C., & Emmerson, E. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.03.009 · Cited by 77
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
The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms
Traustadóttir, G. Á., Lagoni, L. V., Ankerstjerne, L. B. S., Bisgaard, H. C., Jensen, C. H., & Andersen, D. C. (2019) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.03.006 · Cited by 73
Next-Generation Liver Medicine Using Organoid Models
Akbari, S., Arslan, N., Senturk, S., & Erdal, E. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00345 · Cited by 72
Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling
Rosenberg, N., Van Haele, M., Lanton, T., Brashi, N., Bromberg, Z., Adler, H., Giladi, H., Peled, A., Goldenberg, D. S., Axelrod, J. H., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.07.029 · Cited by 72
Genomic Profiling and Metabolic Homeostasis in Primary Liver Cancers
Gingold, J. A., Zhu, D., Lee, D., Kaseb, A. O., & Chen, J. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.02.006 · Cited by 72
Recent Advances in Understandings Towards Pathogenesis and Treatment for Intrauterine Adhesion and Disruptive Insights from Single-Cell Analysis
Leung, R. K., Lin, Y., & Liu, Y. (2020) · Reproductive Sciences · doi:10.1007/s43032-020-00343-y · Cited by 73
Liver cell therapy: is this the end of the beginning?
Alwahsh, S. M., Rashidi, H., & Hay, D. C. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2713-8 · Cited by 71
Specificity and off-target effects of AAV8-TBG viral vectors for the manipulation of hepatocellular gene expression in mice
Kiourtis, C., Wilczynska, A., Nixon, C., Clark, W. A., May, S., & Bird, T. G. (2021) · Biology Open · doi:10.1242/bio.058678 · Cited by 70
Mammalian Target of Rapamycin Complex 1 Signaling Is Required for the Dedifferentiation From Biliary Cell to Bipotential Progenitor Cell in Zebrafish Liver Regeneration
He, J., Chen, J., Wei, X., Leng, H., Mu, H., Cai, P., & Luo, L. (2019) · Hepatology · doi:10.1002/hep.30790 · Cited by 69
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 69
Bavachinin protects the liver in NAFLD by promoting regeneration via targeting PCNA
Dong, X., Lu, S., Tian, Y. T., Ma, H., Wang, Y., Zhang, X., Sun, G., Luo, Y., & Sun, X. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.02.007 · Cited by 69
Tissue regeneration: Reserve or reverse?
Shivdasani, R. A., Clevers, H. C., & de Sauvage, F. J. (2021) · Science · doi:10.1126/science.abb6848 · Cited by 68
Cellular and molecular basis of liver regeneration
Bangru, S., & Kalsotra, A. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.12.004 · Cited by 67

Authors: 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., Kotelevtsev, Y., ffrench-Constant, C., Boulter, L., & Forbes, S. J.
Affiliations: MRC Centre for Regenerative Medicine (GB)
Institute of Genetics and Cancer (GB)
Koch Institute for Integrative Cancer Research At MIT (US)
Skolkovo Institute of Science and Technology (RU)
Corresponding author: Forbes, Stuart J.
ORCID: Raven, Alexander
Lu, Wei-Yu
Man, Tak Yung
O’Duibhir, Eoghan
Dwyer, Benjamin J.
Thomson, John P.
Meehan, Richard R.
Bogorad, Roman
Kotelevtsev, Yuri
Boulter, Luke
Forbes, Stuart J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-07-12
Volume: 547
Issue: 7663
Pages: 350-354
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature23015
PMC: PMC5522613
OpenAlex: W2734880494
Cited by: 533
References: 30
Citations by year: 2026: 32 · 2025: 47 · 2024: 47 · 2023: 62 · 2022: 56 · 2021: 80 · 2020: 79 · 2019: 62 · 2018: 61 · 2017: 7
FWCI: 35.32
Type: journal article
Language: en
Update notices: erratum (2018-03-15)
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders: UK Regenerative Medicine Platform (K026666, MR/K026666/1, MR/L012766/1)
Medical Research Council (MR/L012766/1, MR/K026666, MC_PC_U127574433, MR/K017047/1, MR/K026666/1)
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: cholangiocytes, hepatocyte regeneration, liver injury, beta1 integrin, p21, cell cycle inhibition, ductular reaction, hepatocyte proliferation, chronic liver disease, lineage tracing
MeSH terms: Animals, Bile Ducts, Intrahepatic, Female, Liver, Liver Diseases, Liver Regeneration, Male, Mice, Inbred C57BL, Stem Cells, Integrin beta1, Cell Lineage, Hepatocytes, Cell Proliferation, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks