The biliary epithelium gives rise to liver progenitor cells
Open accessAbstract
Severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in hepatic injury remains a contentious topic. We found that ductular reaction cells in human cirrhotic livers express hepatocyte nuclear factor 1 homeobox B (HNF1β). However, HNF1β expression was not present in newly generated epithelial cell adhesion molecule (EpCAM)-positive hepatocytes. In order to investigate the role of HNF1β-expressing cells we used a tamoxifen-inducible Hnf1βCreER/R26R Yfp/LacZ mouse to lineage-trace Hnf1β+ biliary duct cells and to assess their contribution to LPC expansion and hepatocyte generation. Lineage tracing demonstrated no contribution of HNF1β+ cells to hepatocytes during liver homeostasis in healthy mice or after loss of liver mass. After acute acetaminophen or carbon tetrachloride injury no contribution of HNF1β+ cells to hepatocyte was detected. We next assessed the contribution of Hnf1β+-derived cells following two liver injury models with LPC expansion, a diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet and a choline-deficient ethionine-supplemented (CDE)-diet. The contribution of Hnf1β+ cells to liver regeneration was dependent on the liver injury model. While no contribution was observed after DDC-diet treatment, mice fed with a CDE-diet showed a small population of hepatocytes derived from Hnf1β+ cells that were expanded to 1.86% of total hepatocytes after injury recovery. Genome-wide expression profile of Hnf1β+-derived cells from the DDC and CDE models indicated that no contribution of LPC to hepatocytes was associated with LPC expression of genes related to telomere maintenance, inflammation, and chemokine signaling pathways. Conclusion: HNF1β+ biliary duct cells are the origin of LPC. HNF1β+ cells do not contribute to hepatocyte turnover in the healthy liver, but after certain liver injury, they can differentiate to hepatocytes contributing to liver regeneration. (Hepatology 2014;60:1367–1377)
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The liver repopulating capacity of these HPCs in healthy liver is probably negligible.
“Furthermore, the liver repopulating capacity of these cells in a healthy liver is likely insignificant- previous lineage tracing studies have shown no contribution from HPCs to hepatocytes in healthy liver11,44 and hepatocytes are the primary source of regeneration in normal liver homeostasis3.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [44]
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Cites
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 · see citing works
Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.722 · Cited by 830 · see citing works
Boulter, L., Govaere, O., Bird, T. G., Radulescu, S., Ramachandran, P., Pellicoro, A., Ridgway, R. A., Seo, S. S., Spee, B., Van Rooijen, N., et al. (2012) · Nature Medicine · doi:10.1038/nm.2667 · Cited by 747 · see citing works
Roskams, T., Theise, N. D., Balabaud, C. P., Bhagat, G., Bhathal, P. S., Bioulac‐Sage, P., Brunt, E. M., Crawford, J. M., Crosby, H. A., Desmet, V. J., et al. (2004) · Hepatology · doi:10.1002/hep.20130 · Cited by 729 · see citing works
Human hepatic stem cells from fetal and postnatal donors
Schmelzer, E., Zhang, L., Bruce, A., Wauthier, E., Ludlow, J. W., Yao, H.-L., Moss, N., Melhem, A., McClelland, R., Turner, W. S., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061603 · Cited by 585 · see citing works
Stem Cells and Liver Regeneration
Duncan, A. W., Dorrell, C., & Grompe, M. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.05.044 · Cited by 547 · see citing works
Solar, M., Cardalda, C., Houbracken, I., Martín, M., Maestro, M., Demedts, N., Xu, X.-B., Grau, V., Heimberg, H., Bouwens, L., et al. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.11.003 · Cited by 516 · see citing works
Self-citationLiver Progenitor Cells Yield Functional Hepatocytes in Response to Chronic Liver Injury in Mice
Español–Suñer, R., Carpentier, R., Van Hul, N., Legry, V., Achouri, Y., Cordi, S., Jacquemin, P., Lemaigre, F., & Leclercq, I. A. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.08.024 · Cited by 356 · see citing works
Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β
Coffinier, C., Gresh, L., Fiette, L., Tronche, F., Schütz, G., Babinet, C., Pontoglio, M., Yaniv, M., & Barra, J. (2002) · Development · doi:10.1242/dev.129.8.1829 · Cited by 354 · see citing works
Human Hepatic Stem Cell and Maturational Liver Lineage Biology Δ
Turner, R., Lozoya, O. A., Wang, Y., Cardinale, V., Gaudio, E., Alpini, G. D., Mendel, G., Wauthier, E., Barbier, C., Alvaro, D., et al. (2011) · Hepatology · doi:10.1002/hep.24157 · Cited by 316 · see citing works
Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver
Okabe, M., Tsukahara, Y., Tanaka, M., Suzuki, K., Saito, S., Kamiya, Y., Tsujimura, T., Nakamura, K., & Miyajima, A. (2009) · Development · doi:10.1242/dev.031369 · Cited by 287 · see citing works
Ductular reactions in human liver: Diversity at the interface
Gouw, A. S. H., Clouston, A. D., & Theise, N. D. (2011) · Hepatology · doi:10.1002/hep.24613 · Cited by 275 · see citing works
Carpentier, R., Español‐Suñer, R., Hul, N. V., Kopp, J. L., Beaudry, J., Cordi, S., Antoniou, A., Raynaud, P., Lepreux, S., Jacquemin, P., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.049 · Cited by 271 · see citing works
The stem cell niche of human livers: Symmetry between development and regeneration
Zhang, L., Theise, N. D., Chua, M., & Reid, L. M. (2008) · Hepatology · doi:10.1002/hep.22516 · Cited by 259 · see citing works
Sancho‐Bru, P., Altamirano, J., Rodrigo‐Torres, D., Coll, M., Millán, C., Lozano, J. J., Miquel, R., Arroyo, V., Caballería, J., Ginès, P., et al. (2012) · Hepatology · doi:10.1002/hep.25614 · Cited by 225 · see citing works
Self-citationGuy, C. D., Suzuki, A., Zdanowicz, M., Abdelmalek, M. F., Burchette, J. L., Ünalp, A., & Diehl, A. M. (2011) · Hepatology · doi:10.1002/hep.25559 · Cited by 217 · see citing works
Akhurst, B., Croager, E. J., Farley-Roche, C. A., Ong, J., Dumble, M. L., Knight, B., & Yeoh, G. C. (2001) · Hepatology · doi:10.1053/jhep.2001.26751 · Cited by 212 · see citing works
Smoothened is a master regulator of adult liver repair
Michelotti, G. A., Xie, G., Swiderska, M., Choi, S. S., Karaca, G., Krüger, L., Premont, R. T., Yang, L., Syn, W., METZGER, D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66904 · Cited by 208 · see citing works
Regeneration of hepatocyte ‘buds’ in cirrhosis from intrabiliary stem cells
Falkowski, O., An, H. J., Ianus, I. A., Chiriboga, L. A., Yee, H. T., West, A. B., & Theise, N. D. (2003) · Journal of Hepatology · doi:10.1016/s0168-8278(03)00309-x · Cited by 202 · see citing works
Fate-Mapping Evidence That Hepatic Stellate Cells Are Epithelial Progenitors in Adult Mouse Livers
Yang, L., Jung, Y., Omenetti, A., Witek, R. P., Choi, S. S., VanDongen, H. M. A., Huang, J., Alpini, G. D., & Diehl, A. M. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0115 · Cited by 200 · see citing works
Preisegger, K., Factor, V. M., Fuchsbichler, A., Stumptner, C., Denk, H., & Thorgeirsson, S. S. (1999) · PubMed · Cited by 194 · see citing works
Osteopontin, intrinsic tissue regulator of intractable inflammatory diseases
Uede, T. (2011) · Pathology international (Print) · doi:10.1111/j.1440-1827.2011.02649.x · Cited by 182 · see citing works
Yoon, S.-M., Gerasimidou, D., Kuwahara, R., Hytiroglou, P., Yoo, J. E., Park, Y. N., & Theise, N. D. (2011) · Hepatology · doi:10.1002/hep.24122 · Cited by 177 · see citing works
Novel hepatic progenitor cell surface markers in the adult rat liver
Yovchev, M. I., Grozdanov, P. N., Joseph, B., Gupta, S. K., & Dabeva, M. D. (2006) · Hepatology · doi:10.1002/hep.21448 · Cited by 171 · see citing works
Liver regeneration in acute severe liver impairment: a clinicopathological correlation study
Katoonizadeh, A., Nevens, F., Verslype, C., Pirenne, J., & Roskams, T. (2006) · Liver International · doi:10.1111/j.1478-3231.2006.01377.x · Cited by 171 · see citing works
Suzuki, A., Sekiya, S., Onishi, M., Oshima, N., Kiyonari, H., Nakauchi, H., & Taniguchi, H. (2008) · Hepatology · doi:10.1002/hep.22558 · Cited by 167 · see citing works
Jung, Y., Brown, K. D., Witek, R. P., Omenetti, A., Yang, L., Vandongen, M., Milton, R. J., Hines, I. N., Rippe, R. A., Spahr, L., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.02.022 · Cited by 167 · see citing works
Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potentialPreprint
Shin, S., Walton, G., Aoki, R., Brondell, K., Schug, J., Fox, A., Smirnova, O., Dorrell, C., Erker, L. R., Chu, A. S., et al. (2011) · Genes & Development · doi:10.1101/gad.2027811 · Cited by 153 · see citing works
Foxl1 is a marker of bipotential hepatic progenitor cells in mice†
Sackett, S. D., Li, Z., Hurtt, R., Gao, Y., Wells, R. G., Brondell, K., Kaestner, K. H., & Greenbaum, L. E. (2008) · Hepatology · doi:10.1002/hep.22705 · Cited by 141 · see citing works
Raynaud, P., Tate, J. M., Callens, C., et al. (2011) · Hepatology · doi:10.1002/hep.24292 · Cited by 114 · see citing works
Crucial role of vHNF1 in vertebrate hepatic specification
Lokmane, L., Haumaître, C., García-Villalba, P., Anselme, I., Schneider-Maunoury, S., & Cereghini, S. (2008) · Development · doi:10.1242/dev.023010 · Cited by 106 · see citing works
Yamasaki, H., Sada, A., Iwata, T., Niwa, T., Tomizawa, M., Xanthopoulos, K. G., Koike, T., & Shiojiri, N. (2006) · Development · doi:10.1242/dev.02591 · Cited by 99 · see citing works
Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis
Morales‐Ibanez, O., Domínguez, M., Ki, S. H., Marcos, M., Chaves, F. J., Nguyen-Khac, É., Houchi, H., Affò, S., Sancho‐Bru, P., Altamirano, J., et al. (2013) · Hepatology · doi:10.1002/hep.26521 · Cited by 97 · see citing works
Self-citationIsse, K., Lesniak, A. J., Grama, K., Maier, J., Specht, S. M., Castillo‐Rama, M., Lunz, J. G., Roysam, B., Michalopoulos, G. K., & Demetris, A. J. (2012) · Hepatology · doi:10.1002/hep.26131 · Cited by 50 · see citing works
Enrichment of Hepatic Progenitor Cells From Adult Mouse Liver
Azuma, H., Hirose, T., Fujii, H., et al. (2003) · Hepatology · doi:10.1053/jhep.2003.50210 · Cited by 47 · see citing works
HNF1B deficiency causes ciliary defects in human cholangiocytes
Roelandt, P. R., Antoniou, A., Libbrecht, L. J., et al. (2012) · Hepatology · doi:10.1002/hep.25876 · Cited by 34 · see citing works
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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 · see citing works
Ductular reaction in liver diseases: pathological mechanisms and translational significances
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Gordillo, M., Evans, T., & Gouon-Evans, V. (2015) · Development · doi:10.1242/dev.114215 · Cited by 375 · see citing works
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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
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 · see citing works
Schaub, J. R., Malato, Y., Gormond, C., & Willenbring, H. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.003 · Cited by 254 · see citing works
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 · see citing works
Lineage fate of ductular reactions in liver injury and carcinogenesis
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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 · see citing works
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Michelotti, G. A., Tucker, A., Swiderska-Syn, M., Machado, M. V., Choi, S. S., Kruger, L., Soderblom, E., Thompson, J. W., Mayer-Salman, M., Himburg, H. A., et al. (2016) · Gut · doi:10.1136/gutjnl-2014-308176 · Cited by 40 · see citing works
Guillot, A., Gasmi, I., Brouillet, A., Ait‐Ahmed, Y., Calderaro, J., Ruiz, I., Gao, B., Lotersztajn, S., Pawlotsky, J., & Lafdil, F. (2018) · Hepatology Communications · doi:10.1002/hep4.1145 · Cited by 38 · see citing works
Manco, R., Leclercq, I. A., & Clerbaux, L.-A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19124115 · Cited by 36 · see citing works
Rezvani, M., Vallier, L., & Guillot, A. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.01.014 · Cited by 34 · see citing works
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Zhang, H., Siegel, C. T., Shuai, L., Lai, J., Zeng, L., Zhang, Y., Lai, X., Bie, P., & Bai, L. (2016) · Scientific Reports · doi:10.1038/srep21783 · Cited by 30 · see citing works
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- Authors
- Rodrigo-Torres, D., Affò, S., Coll, M., Morales-Ibanez, O., Millán, C., Blaya, D., Alvarez-Guaita, A., Rentero, C., José Lozano, J., Maestro, M. A., Solar, M., Arroyo, V., Caballería, J., van Grunsven, L. A., Enrich, C., Ginès, P., Bataller, R., & Sancho-Bru, P.
- Affiliations
- Hospital Clínic de Barcelona (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Hepatology
- Published
- 2014-10
- Volume
- 60
- Issue
- 4
- Pages
- 1367-1377
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC4410184
- OpenAlex
- W1948254390
- Cited by
- 189
- References
- 36
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 19 · 2022: 18 · 2021: 8 · 2020: 16 · 2019: 17 · 2018: 22 · 2017: 16 · 2016: 21 · 2015: 19 · 2014: 8
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (1U01AA021908-01)
- Instituto de Salud Carlos III (PI041538, FIS PI12/01274, FIS PS09/01164 and FIS PI080126, Miguel Servet (CP11/00071))
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver progenitor cells, biliary epithelium, HNF1B, hepatocyte differentiation, liver regeneration, liver injury, liver cirrhosis, lineage tracing, choline-deficient ethionine-supplemented diet, hepatocyte turnover
- MeSH terms
- Acetaminophen, Animals, Bile Ducts, Carbon Tetrachloride, Cell Differentiation, Cells, Cultured, Diet, Disease Models, Animal, Epithelial Cells, Female, Homeostasis, Humans, Liver, Liver Regeneration, Male, Mice, Transgenic, Stem Cells, Cell Lineage, Hepatocytes, Mice, Hepatocyte Nuclear Factor 1-beta, Chemical and Drug Induced Liver Injury
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