Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury
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Background & aim Chronic liver diseases are characterized by expansion of the small immature cholangiocytes - a mechanism named ductular reaction (DR) - which have the capacity to differentiate into hepatocytes. We investigated the kinetics of this differentiation, as well as analyzing several important features of the newly formed hepatocytes, such as functional maturity, clonal expansion and resistance to stress in mice with long-term liver damage.Methods We tracked cholangiocytes using osteopontin-iCreER T2 and hepatocytes with AAV8-TBG-Cre. Mice received carbon tetrachloride (CCl 4) for >24 weeks to induce chronic liver injury. Livers were collected for the analysis of reporter proteins, cell proliferation and death, DNA damage, and nuclear ploidy; hepatocytes were also isolated for RNA sequencing.Results During liver injury we observed a transient DR and the differentiation of DR cells into hepatocytes as clones that expanded to occupy 12% of the liver parenchyma by week 8. By lineage tracing, we confirmed that these new hepatocytes derived from cholangiocytes but not from native hepatocytes. They had all the features of mature functional hepatocytes. In contrast to the exhausted native hepatocytes, these newly formed hepatocytes had higher proliferative capability, less apoptosis, a lower proportion of highly polyploid nuclei and were better at eliminating DNA damage.Conclusions In chronic liver injury, DR cells differentiate into stress-resistant hepatocytes that repopulate the liver. The process might account for the observed parenchymal reconstitution in livers of patients with advanced-stage hepatitis and could be a target for regenerative purposes.Lay summary During chronic liver disease, while native hepatocytes are exhausted and genetically unstable, a subset of cholangiocytes clonally expand to differentiate into young, functional and robust hepatocytes. This cholangiocyte cell population is a promising target for regenerative therapies in patients with chronic liver insufficiency.
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BECs and ductular reactions have sparked interest as potential reservoirs of alternative liver progenitor cells, a phenomenon that relies on the participation of innate and adaptive immune cells.
“Moreover, BECs and ductular reactions have sparked interest as potential reservoirs of alternative liver progenitor cells, a phenomenon that also relies on the participation of innate and adaptive immune cells [158–160].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [160]
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Cites
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491 · see citing works
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Srinivas, S., Watanabe, T., Lin, C.-S., William, C. M., Tanabe, Y., Jessell, T. M., & Costantini, F. (2001) · BMC Developmental Biology · doi:10.1186/1471-213x-1-4 · Cited by 3,121 · see citing works
Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system
Livet, J., Weissman, T. A., Kang, H., Draft, R. W., Lu, J., Bennis, R. A., Sanes, J. R., & Lichtman, J. W. (2007) · Nature · doi:10.1038/nature06293 · Cited by 1,876 · see citing works
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
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
Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes
Tarlow, B. D., Pelz, C., Naugler, W. E., Wakefield, L., Wilson, E. M., Finegold, M. J., & Grompe, M. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.09.008 · Cited by 533 · see citing works
Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration
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., et al. (2017) · Nature · doi:10.1038/nature23015 · Cited by 533 · 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
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 · see citing works
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 · see citing works
Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration
Malato, Y., Naqvi, S., Schürmann, N., Ng, R., Wang, B., Zape, J., Kay, M. A., Grimm, D., & Willenbring, H. (2011) · Journal of Clinical Investigation · doi:10.1172/jci59261 · Cited by 434 · see citing works
TWEAK induces liver progenitor cell proliferation
Jakubowski, A., Ambrose, C., Parr, M., Lincecum, J. M., Wang, M. Z., Zheng, T. S., Browning, B., Michaelson, J. S., Baestcher, M., Wang, B., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23486 · Cited by 419 · see citing works
Antoniou, A., Raynaud, P., Cordi, S., Zong, Y., Tronche, F., Stanger, B. Z., Jacquemin, P., Pierreux, C. E., Clotman, F., & Lemaigre, F. P. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.02.051 · Cited by 362 · see citing works
Clouston, A. D., Powell, E. E., Walsh, M. J., Richardson, M. M., Demetris, A. J., & Jonsson, J. R. (2005) · Hepatology · doi:10.1002/hep.20650 · Cited by 361 · see citing works
Liver 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
Self-citationProgenitor Cells in Diseased Human Liver
Roskams, T., Libbrecht, L. J., & Desmet, V. J. (2003) · Seminars in Liver Disease · doi:10.1055/s-2004-815564 · Cited by 337 · see citing works
The global burden of liver disease: a challenge for methods and for public health
Byass, P. (2014) · BMC Medicine · doi:10.1186/s12916-014-0159-5 · Cited by 321 · see citing works
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 · 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
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
Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease
Gentric, G., Maillet, V., Paradis, V., Couton, D., L’Hermitte, A., Panasyuk, G., Fromenty, B., Celton-Morizur, S., & Desdouets, C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73957 · Cited by 240 · see citing works
Self-citationHe, J., Lu, H., Zou, Q., & Luo, L. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.11.045 · Cited by 240 · see citing works
Clonal Tracing of Sox9+ Liver Progenitors in Mouse Oval Cell Injury
Tarlow, B., Finegold, M. J., & Grompe, M. (2014) · Hepatology · doi:10.1002/hep.27084 · Cited by 220 · see citing works
Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment
Mu, X., Español‐Suñer, R., Mederacke, I., Affò, S., Manco, R., Sempoux, C. L., Lemaigre, F. P., Adili, A., Yuan, D., Weber, A., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77995 · Cited by 214 · see citing works
Self-citationRegeneration 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
Polyploidization in Liver Tissue
Gentric, G., & Desdouets, C. (2014) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.06.035 · Cited by 192 · see citing works
Self-citationThe biliary epithelium gives rise to liver progenitor cells
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., et al. (2014) · Hepatology · doi:10.1002/hep.27078 · Cited by 189 · 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
Hul, N. V., Abarca‐Quinones, J., Sempoux, C. L., Horsmans, Y., & Leclercq, I. A. (2009) · Hepatology · doi:10.1002/hep.22820 · Cited by 162 · see citing works
Self-citationParacrine cellular senescence exacerbates biliary injury and impairs regeneration
Ferreira-Gonzalez, S., Lu, W.-Y., Raven, A., Dwyer, B., Man, T. Y., O’Duibhir, E., Lewis, P. J. S., Campana, L., Kendall, T. J., Bird, T. G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03299-5 · Cited by 161 · see citing works
Lineage fate of ductular reactions in liver injury and carcinogenesis
Jörs, S., Jeliazkova, P., Ringelhan, M., Thalhammer, J., Dürl, S., Ferrer, J., Sander, M., Heikenwalder, M., Schmid, R. M., Siveke, J. T., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci78585 · Cited by 149 · see citing works
Firsanov, D., Solovjeva, L. V., & Svetlova, M. (2011) · Clinical Epigenetics · doi:10.1007/s13148-011-0044-4 · Cited by 139 · see citing works
Tummala, K. S., Brandt, M., Teijeiro, A., Graña‐Castro, O., Schwabe, R. F., Perna, C., & Djouder, N. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.03.059 · Cited by 138 · see citing works
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 137 · see citing works
Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration
Pu, W., Zhang, H., Huang, X., Tian, X., He, L., Wang, Y., Zhang, L., Liu, Q., Li, Y., Li, Y., et al. (2016) · Nature Communications · doi:10.1038/ncomms13369 · Cited by 136 · see citing works
Sekiya, S., & Suzuki, A. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.01.005 · Cited by 125 · see citing works
Stueck, A., & Wanless, I. R. (2015) · Hepatology · doi:10.1002/hep.27706 · Cited by 109 · see citing works
Kamimoto, K., Kaneko, K., Kok, C., Okada, H., Miyajima, A., & Itoh, T. (2016) · eLife · doi:10.7554/elife.15034 · Cited by 104 · see citing works
the Histogenesis of Regenerative Nodules in Human Liver Cirrhosis
Lin, W., Lim, S., McDonald, S. A. C., Graham, T. A., Wright, V. L., Peplow, C. L., Humphries, A., Kocher, H. M., Wright, N. A., Dhillon, A. P., et al. (2009) · Hepatology · doi:10.1002/hep.23483 · Cited by 99 · see citing works
Progenitor cell involvement in cirrhotic human liver diseases: from controversy to consensus
Roskams, T. (2003) · Journal of Hepatology · doi:10.1016/s0168-8278(03)00333-7 · Cited by 94 · see citing works
MicroRNA‐122 regulates polyploidization in the murine liver
Hsu, S., Delgado, E. R., Otero, P. A., Teng, K., Kutay, H., Meehan, K. M., Moroney, J. B., Monga, J. K., Hand, N. J., Friedman, J. R., et al. (2016) · Hepatology · doi:10.1002/hep.28573 · Cited by 84 · see citing works
Hepatic Progenitor Cells: An Update
Roskams, T., Katoonizadeh, A., & Komuta, M. (2010) · Clinics in Liver Disease · doi:10.1016/j.cld.2010.08.003 · Cited by 72 · see citing works
Adult Mouse Liver Contains Two Distinct Populations of Cholangiocytes
Li, B., Dorrell, C., Canaday, P. S., Pelz, C., Haft, A., Finegold, M. J., & Grompe, M. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.06.003 · Cited by 66 · see citing works
Dynamics of Proliferative and Quiescent Stem Cells in Liver Homeostasis and Injury
Cao, W., Chen, K., Bolkestein, M., Yin, Y., Verstegen, M. M. A., Bijvelds, M. J. C., Wang, W., Tüysüz, N., ten Berge, D., Sprengers, D., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.07.006 · Cited by 47 · see citing works
Haele, M. V., & Roskams, T. (2017) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2017.01.011 · Cited by 39 · see citing works
Decoding development in Xenopus tropicalis
Showell, C., & Conlon, F. L. (2007) · genesis · doi:10.1002/dvg.20286 · Cited by 25 · see citing works
Functionality based method for simultaneous isolation of rodent hepatic sinusoidal cells
Stradiot, L., Verhulst, S., Roosens, T., Øie, C. I., Moya, I. M., Halder, G. A., Mannaerts, I., & van Grunsven, L. A. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.05.047 · Cited by 17 · see citing works
Self-citationThe Applicability of a Human Immunohistochemical Panel to Mouse Models of Hepatocellular Neoplasia.
Salleng, K. J., Revetta, F. L., Deane, N. G., & Washington, M. K. (2015) · PubMed Central · Cited by 9 · see citing works
Flagged first, then by citations
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- Roskams TA, Theise ND, Balabaud C, et al. Nomenclature of the Finer Branches of the Biliary. Hepatology 2004;39:1739-1745.
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Sorted by citations
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 · 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
Spatial sorting enables comprehensive characterization of liver zonation
Ben-Moshe, S., Shapira, Y., Moor, A. E., Manco, R., Veg, T., Bahar Halpern, K., & Itzkovitz, S. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0109-9 · Cited by 205 · see citing works
Self-citationSpatial sorting enables comprehensive characterization of liver zonation
Ben-Moshe, S., Shapira, Y., Moor, A. E., Halpern, K. B., & Itzkovitz, S. (2019) · doi:10.1101/529784 · Cited by 205 · 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
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 · see citing works
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 · see citing works
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 114 · see citing works
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 113 · see citing works
McCarron, S., Bathon, B., Conlon, D. M., Abbey, D., Rader, D. J., Gawronski, K., Brown, C. D., Olthoff, K. M., Shaked, A., & Raabe, T. D. (2021) · Hepatology · doi:10.1002/hep.31857 · Cited by 89 · see citing works
Jung, K., Kim, M., So, J., Lee, S., Ko, S., & Shin, D. (2020) · Hepatology · doi:10.1002/hep.31679 · Cited by 80 · see citing works
NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis
Huang, B., Lyu, Z., Qian, Q., Chen, Y., Zhang, J., Li, B., Li, Y., Liang, J., Liu, Q., Li, Y., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.06.014 · Cited by 60 · 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
Spatial discordances between mRNAs and proteins in the intestinal epithelium
Harnik, Y., Buchauer, L., Ben‐Moshe, S., Averbukh, I., Levin, Y., Savidor, A., Eilam, R., Moor, A. E., & Itzkovitz, S. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00504-6 · Cited by 56 · see citing works
Rizvi, F., Lee, Y., Díaz‐Aragon, R., Bawa, P., So, J., Florentino, R. M., Wu, S. Y., Sarjoo, A., Truong, E., Smith, A. R., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.10.008 · Cited by 59 · 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
Ishtiaq, S. M., Arshad, M. I., & Khan, J. A. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108298 · Cited by 49 · see citing works
So, J., Kim, M., Lee, S., Ko, S., Lee, D. A., Park, H., Azuma, M., Parsons, M. J., Prober, D. A., & Shin, D. (2020) · Hepatology · doi:10.1002/hep.31437 · Cited by 46 · see citing works
Signaling pathways of liver regeneration: Biological mechanisms and implications
Zhang, C., Sun, C., Zhao, Y., Ye, B., & Yu, G. (2023) · iScience · doi:10.1016/j.isci.2023.108683 · Cited by 48 · see citing works
Ghallab, A., Myllys, M., Friebel, A., Duda, J., Edlund, K., Halilbasic, E., Vucur, M., Hobloss, Z., Brackhagen, L., Begher‐Tibbe, B., et al. (2021) · Cells · doi:10.3390/cells10102516 · Cited by 39 · 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
Clerbaux, L., Manco, R., Hul, N. V., Bouzin, C., Sciarra, A., Sempoux, C. L., Theise, N. D., & Leclercq, I. A. (2019) · American Journal Of Pathology · doi:10.1016/j.ajpath.2019.04.011 · Cited by 38 · see citing works
Self-citationHepatic NAPE-PLD Is a Key Regulator of Liver Lipid Metabolism
Lefort, C., Roumain, M., Hul, M. V., Rastelli, M., Manco, R., Leclercq, I. A., Delzenne, N. M., Marzo, V. D., Flamand, N., Luquet, S. H., et al. (2020) · Cells · doi:10.3390/cells9051247 · Cited by 33 · see citing works
Self-citationDistinct hepatocyte identities in liver homeostasis and regeneration
Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30 · see citing works
Recent advances in tissue stem cells
Fu, X., He, Q., Tao, Y., Wang, M., Wang, W., Wang, Y., Yu, Q. C., Zhang, F., Zhang, X., Chen, Y., et al. (2021) · Science China Life Sciences · doi:10.1007/s11427-021-2007-8 · Cited by 29 · see citing works
Oderberg, I. M., & Goessling, W. (2023) · JCI Insight · doi:10.1172/jci.insight.163929 · Cited by 29 · see citing works
Hepatocyte generation in liver homeostasis, repair, and regeneration
Pu, W., & Zhou, B. (2022) · Cell Regeneration · doi:10.1186/s13619-021-00101-8 · Cited by 25 · see citing works
Is liver regeneration key in hepatocellular carcinoma development?
Rigual, M. D. M., Sánchez, P. S., & Djouder, N. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.10.005 · Cited by 27 · 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
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 27 · see citing works
Xiang, X., He, Y., Zhang, Z., & Yang, X. (2024) · Nature Communications · doi:10.1038/s41467-024-46480-9 · Cited by 23 · 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
Dynamics of hepatocyte-cholangiocyte cell-fate decisions during liver development and regeneration
Sahoo, S., Mishra, A., Diehl, A. M., & Jolly, M. K. (2022) · iScience · doi:10.1016/j.isci.2022.104955 · Cited by 23 · see citing works
Microenvironmental control of the ductular reaction: balancing repair and disease progression
Sorrentino, G. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07590-4 · Cited by 23 · see citing works
Dissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics
Colella, F., Henderson, N. C., & Ramachandran, P. (2025) · Journal of Clinical Investigation · doi:10.1172/jci186421 · Cited by 22 · 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
Sox9EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity
Tulasi, D. Y., Castaneda, D. M., Wager, K., Hogan, C. B., Alcedo, K. P., Raab, J. R., & Gracz, A. D. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.01.009 · Cited by 18 · see citing works
Biglycan promotes hepatic fibrosis through activating heat shock protein 47
Yu, M., He, X., Song, X., Gao, J., Pan, J., Zhou, T., Wang, Q., Zhu, W., Ma, H., Zeng, H., et al. (2022) · Liver International · doi:10.1111/liv.15477 · Cited by 19 · see citing works
DNA methylation in cell plasticity and malignant transformation in liver diseases
Kim, M., Delgado, E. R., & Ko, S. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108334 · Cited by 20 · see citing works
Ma, J., Yang, Z., Huang, Z., Li, L., Huang, J., Chen, J., Ni, R., Luo, L., & He, J. (2023) · Hepatology · doi:10.1097/hep.0000000000000186 · Cited by 16 · see citing works
Eski, S. E., Mi, J., Pozo‐Morales, M., Hovhannisyan, G., Perazzolo, C., Manco, R., Ez-Zammoury, I., Barbhaya, D., Lefort, A., Libert, F., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60334-y · Cited by 18 · see citing works
Self-citationContributions 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
DNA methylation maintenance at the p53 locus initiates biliary-mediated liver regeneration
He, J., Zhou, Y., Qian, C., Wang, D., Yang, Z., Huang, Z., Sun, J., Ni, R., Yang, Q., Chen, J., et al. (2022) · npj Regenerative Medicine · doi:10.1038/s41536-022-00217-8 · Cited by 16 · 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
Lou, C., Lan, T., Xu, S., Hu, X., Li, J., Xiang, Z., Lin, S., Fan, X., Chen, J., & Xu, X. (2025) · Gut · doi:10.1136/gutjnl-2025-334763 · Cited by 15 · see citing works
Huang, W., Qiu, B., Qi, X.-S., Chen, C., Liu, W., Zhou, S.-A., Ding, M., Lu, F., Zhao, J., Tang, D., et al. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01123-2 · Cited by 14 · see citing works
Pennisi, G., Pipitone, R. M., Cabibi, D., Enea, M., Romero‐Gómez, M., Viganò, M., Bugianesi, E., Wong, V. W., Fracanzani, A. L., Sebastiani, G., et al. (2022) · Liver International · doi:10.1111/liv.15232 · Cited by 13 · see citing works
Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles
Verhulst, S., Roskams, T., Sancho‐Bru, P., & van Grunsven, L. A. (2019) · Cells · doi:10.3390/cells8101117 · Cited by 13 · see citing works
Self-citationKim, M., So, J., & Shin, D. (2023) · Scientific Reports · doi:10.1038/s41598-023-44935-5 · Cited by 9 · see citing works
Role of mitogens in normal and pathological liver regeneration
Vosough, M., Shokouhian, B., Sharbaf, M. A., Solhi, R., Heidari, Z., Seydi, H., Hassan, M., Ezhilarasan, D., & Najimi, M. (2025) · Hepatology Communications · doi:10.1097/hc9.0000000000000692 · Cited by 8 · see citing works
Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
Yıldız, E., Alam, G. E., Perino, A., Jalil, A., Denechaud, P., Huber, K., Fajas, L., Auwerx, J. H., Sorrentino, G., & Schoonjans, K. (2022) · eLife · doi:10.7554/elife.81926 · Cited by 10 · see citing works
Babboni, S., Vacca, P. G., Simonini, L., Pezzati, D., Martinelli, C., Frongillo, F., Bianco, G., Marciano, E., Basta, G., Ghinolfi, D., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13061804 · Cited by 7 · see citing works
The Progress and Promise of Lineage Reprogramming Strategies for Liver Regeneration
Wang, S., Wang, X., & Wang, Y. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.101395 · Cited by 7 · see citing works
Using different zebrafish models to explore liver regeneration
Mo, D., Lv, M., & Mao, X. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1485773 · Cited by 6 · see citing works
Dong, A., Wei, G., Liang, Z., Di, Y., Tang, Y., Ling, Y., Li, S., Chen, Y., Zhou, Y., Wang, X., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61397-7 · Cited by 8 · see citing works
Aoshima, K., & Tanimizu, N. (2025) · Regenerative Therapy · doi:10.1016/j.reth.2025.04.008 · Cited by 6 · see citing works
Milani, M., Starinieri, F., Fabiano, A., Beretta, S., Plati, T., Canepari, C., Biffi, M., Russo, F., Berno, V., Norata, R., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115341 · Cited by 4 · see citing works
Update on Hepatobiliary Plasticity
Kim, M., Rizvi, F., Shin, D., & Gouon–Evans, V. (2023) · Seminars in Liver Disease · doi:10.1055/s-0042-1760306 · Cited by 4 · see citing works
Cell identity conversion in liver regeneration after injury
He, Q., Cui, L., Yuan, X., Wang, M., & Hui, L. (2022) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2022.101921 · Cited by 4 · see citing works
Biliary-derived hepatocytes in chronic liver injury: Bringing new troops to the battlefield?
Aleksieva, N., & Forbes, S. J. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.03.015 · Cited by 4 · see citing works
Valle-Encinas, E., Aleksieva, N., Martinez, C. V., Dawes, M., Zverev, M., Müller, M., Offergeld, A., Smalley, M. J., Hogan, C., Forbes, S. J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.09.374462 · Cited by 4 · see citing works
Pehlivanoğlu, B., Aysal, A., Ağalar, C., Egeli, T., Özbilgin, M., Ünek, T., Unek, T., Öztop, İ., & Sağol, Ö. (2022) · Apmis · doi:10.1111/apm.13220 · Cited by 3 · see citing works
Cabibi, D., Giannone, A. G., Quattrocchi, A., Calvaruso, V., Porcasi, R., Grusa, D. D., Pavone, A. M., Comelli, A., & Petta, S. (2024) · Biomedicines · doi:10.3390/biomedicines12020440 · Cited by 3 · see citing works
Ambrosio, E. M., Bailey, C. S. L., Unterweger, I. A., Christensen, J. B., Bruchez, M. P., Lundegaard, P. R., & Ober, E. A. (2024) · Development · doi:10.1242/dev.202217 · Cited by 3 · see citing works
The influence of tissue spatial geometry and functional organisation on liver regeneration
Aloia, L. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.09.011 · Cited by 3 · see citing works
Recent Advances in Intrahepatic Biliary Epithelial Heterogeneity
Little, A., Medford, A., O’Brien, A., Childs, J. R., Pan, S., Machado, J., Chakraborty, S., & Glaser, S. S. (2022) · Seminars in Liver Disease · doi:10.1055/s-0042-1758833 · Cited by 3 · see citing works
Jiroušková, M., Harant, K., Cejnar, P., Ojha, S., Korelova, K., Sarnová, L., Sticová, E., Mayr, C. H., Schiller, H. B., & Gregor, M. (2024) · eLife · doi:10.7554/elife.98023 · Cited by 3 · see citing works
Zhang, L., Xiong, Z., Chen, Z., Xu, M., Zhao, S., Liu, X., Jiang, K., Hu, Y., Liu, S., Sun, X., et al. (2025) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2025.101498 · Cited by 2 · see citing works
Triggering Mechanisms of Hepatocyte Repopulation during Liver Regeneration
Lee, E. J., Lee, N. Y., Choi, M. G., Ryu, H. J., & Koo, J. H. (2025) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2025.035 · Cited by 2 · see citing works
Liver sinusoidal endothelial cells and laminin dictate cholangiocytes’ fate in chronic liver disease
Manco, R., Moliterni, C., Neirynck, G., Claus, R., Rudder, M. D., Picalausa, C., Ducor, L., Fraga, M., Coubeau, L., Dongier, A., et al. (2026) · Journal of Hepatology · doi:10.1016/j.jhep.2026.03.022 · Cited by 2 · see citing works
Self-citationAberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors
Nishikawa, Y. (2024) · Pathology International · doi:10.1111/pin.13441 · Cited by 1 · see citing works
Setd4-expressing cells drive regenerative recovery in chronic liver injury
Jia, X.-Z., Zhuang, T.-T., Yang, R.-S., Gu, Y.-W., Zeng, Y.-Z., Wood, C., Yang, J., & Yang, W. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.09.034 · Cited by 1 · see citing works
Osteopontin: a central hub in the pathogenesis and therapeutic intervention of liver disease
Yang, J., Yao, Y., & Zhou, Z. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2596538 · Cited by 1 · see citing works
Антонова, Е. И., Omarova, D. I., Firsova, N. V., & Krasnikova, K. A. (2024) · Učënye zapiski Kazanskogo universiteta. Seriâ Estestvennye nauki/Učënye zapiski Kazanskogo universiteta. Seriâ Estestvennye nauki/Učenye zapiski Kazanskogo gosudarstvennogo universiteta. Seriâ Estestvennye nauki · doi:10.26907/2542-064x.2024.1.38-65 · Cited by 1 · see citing works
Gonçalves, J. D. O., Mafra, C. A. M., de Castro, I., Cogliati, B., Teodoro, W. R., Bando, S. Y., Serafini, S., Moreira‐Filho, C. A., Tannuri, U., & Tannuri, A. C. A. (2025) · Pediatric Research · doi:10.1038/s41390-025-04272-x · Cited by 1 · see citing works
Rodríguez‐Aguilera, J. R., Ecsedi, S., Cros, M., Goldsmith, C., Domínguez-López, M., Guerrero‐Celis, N., de Vaca, R. P., Chemin, I., Targa, F. R., de Sánchez, V. C., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/629493 · Cited by 1 · see citing works
NASH patient liver derived organoids exhibit patient specific NASH phenotypes and drug responsesPreprint
McCarron, S., Bathon, B. E., Abbey, D., Conlon, D., Rader, D. J., Olthoff, K. M., Shaked, A. A., & Raabe, T. D. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/791467 · Cited by 1 · see citing works
Liver Sinusoidal Endothelial Cells and Laminin dictate cholangiocytes’ fate in chronic liver diseasePreprint
Manco, R., Moliterni, C., Neirynck, G., Rudder, M. D., Picalausa, C., Ducor, L., Fraga, M., Lemaigre, F. P., Sempoux, C. L., Dili, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.29.615650 · Cited by 1 · see citing works
Self-citationJiroušková, M., Harant, K., Cejnar, P., Ojha, S., Korelova, K., Sarnová, L., Sticová, E., Mayr, C. H., Schiller, H. B., & Gregor, M. (2025) · eLife · doi:10.7554/elife.98023.2 · Cited by 1 · see citing works
Ishtiaq, S. M., Arshad, M. I., & Khan, J. A. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4192515
Jiroušková, M., Harant, K., Cejnar, P., Ojha, S., Korelova, K., Sarnová, L., Sticová, E., Mayr, C. H., Schiller, H. B., & Gregor, M. (2025) · eLife · doi:10.7554/elife.98023.3
Jiroušková, M., Harant, K., Cejnar, P., Ojha, S., Korelova, K., Sarnová, L., Sticová, E., Mayr, C. H., Schiller, H. B., & Gregor, M. (2024) · eLife · doi:10.7554/elife.98023.1
Антонова, Е. И., Omarova, D. I., Firsova, N. V., & Ачилов, А. Б. (2025) · Biological Communications · doi:10.21638/spbu03.2024.403
Assessment of the Impact of Pfas on Liver Functions Using OrganoidsPreprint
Zhao, J., Cheng, X., Chen, B., Xu, S., & Wu, L. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5265407
Yamamoto, T., Yamaguchi, J., Kokuryo, T., Yokoyama, Y., Mizuno, T., Onoe, S., Sunagawa, M., Baba, T., & Ebata, T. (2025) · Cells · doi:10.3390/cells14171323
Shi, X., Mekis, G., Simms, K. J., Gao, B., & Zhang, P. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108959 · Cited by 1 · see citing works
Huang, W.-J., Qiu, B.-J., Qi, X.-S., Chen, C.-Y., Liu, W.-M., Zhou, S.-A., Ding, M., Lu, F.-F., Zhao, J., Tang, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24234232
Zhang, J., Xu, Y., & Lu, X. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1743286
Wolff, O., Kobe, A. R., Clerbaux, L., Bütikofer, C., Adamczyk, M., Rechsteiner, M., Weber, A., & Friemel, J. (2026) · Laboratory Investigation · doi:10.1016/j.labinv.2026.106122
Self-citationCellCousin2: an optimized system for partial ablation and tracing of regenerative lineages
Hovhannisyan, G., Akhourbi, T., Eski, S. E., Pirson, I., Gurzov, E. N., & Singh, S. P. (2026) · npj Regenerative Medicine · doi:10.1038/s41536-026-00473-y
Sun, C., Yue, M., Chen, Y., Zhang, J., Mai, Y., Zhang, Y., & Ye, B. (2026) · Cell Biochemistry and Function · doi:10.1002/cbf.70320
- Authors
- Manco, R., Clerbaux, L.-A., Verhulst, S., Bou Nader, M., Sempoux, C., Ambroise, J., Bearzatto, B., Gala, J. L., Horsmans, Y., van Grunsven, L., Desdouets, C., & Leclercq, I.
- Affiliations
- UCLouvain (BE)
- Vrije Universiteit Brussel (BE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Cliniques Universitaires Saint-Luc (BE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Leclercq, Isabelle
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 70
- Issue
- 6
- Pages
- 1180-1191
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2915464486
- Cited by
- 92
- References
- 49
- Citations by year
- 2026: 5 · 2025: 21 · 2024: 12 · 2023: 11 · 2022: 14 · 2021: 13 · 2020: 10 · 2019: 6
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Belgian Federal Science Policy Office
- Scientific Medical Research
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- cholangiocytes, ductular reaction, hepatocyte differentiation, chronic liver injury, DNA repair, clonal expansion, hepatocyte regeneration, liver regeneration, hepatocyte proliferation, hepatocyte apoptosis, DNA ploidy, lineage tracing, regenerative therapy, DNA damage
- MeSH terms
- Animals, Bile Ducts, Carbon Tetrachloride, Cell Differentiation, Chronic Disease, DNA Repair, Liver Neoplasms, Polyploidy, Precancerous Conditions, Hepatocytes, Cell Proliferation, Mice, Chemical and Drug Induced Liver Injury
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