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Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration
Open accessAbstract
Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.
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“Through coordination of this and other epigenetics pathways42, YAP activity is able to be amplified robustly to ensure a timely adjustment during liver injury and regeneration.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [42]
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“Pooling together different cells and/or organoids for bulk analysis can lead to inaccurate results3,70,100,204,207,208.”
From Organoids (2022) · cites this paper as [208]
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Role of Immune Cells in Biliary Repair
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Is liver regeneration key in hepatocellular carcinoma development?
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BackgroundTargeting epigenetic alterations in cancer stem cells
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Bioengineered Tubular Biliary Organoids
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Sox9EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity
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DNA methylation in cell plasticity and malignant transformation in liver diseases
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Cell-Based Regeneration and Treatment of Liver Diseases
Hofmann, J. D., Hackl, V., Esser, H., Mészáros, A., Fodor, M., Öfner, D., Troppmair, J., Schneeberger, S., & Hautz, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910276 · Cited by 22
“One of the TET1 targets is the hippo-yes-associated protein (YAP)/PDZ-binding motif (TAZ) pathway [49].”
BackgroundA brief history of testicular organoids: from theory to the wards
Wang, N., Jiaming, S., Minghua, L. I. U., Ma, L., Lina, Q. I. N., Xuemei, G. E., & Hongli, Y. A. N. (2022) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-022-02529-6 · Cited by 17
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ResultAddressing Key Questions in Organoid Models: Who, Where, How, and Why?
Gómez‐Álvarez, M., Agustina‐Hernández, M., Francés‐Herrero, E., Rodríguez‐Eguren, A., Bueno-Fernández, C., & Cervelló, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242116014 · Cited by 18
“…epithelial growth factor (EGF) [52,120,123], hepatocyte growth factor (HGF) [122,124–126], fibroblast growth factor (FGF) [52,118,124,127–129], transforming growth factor alpha (TGF α ) [39], gastrin [52,120,122], bone morphogenetic protein 4 (BMP4) [130–132], and Wnt [117,118,120,131].”
BackgroundLiver organoids: From fabrication to application in liver diseases
Liu, Q., Zeng, A., Liu, Z., Wu, C., & Song, L. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.956244 · Cited by 19
“After the liver organoid is generated, its performance can usually be assessed in vitro bymorphological tests (Broutier et al., 2016; Aloia et al., 2019; Ogoke et al., 2022), functional tests (Akbari et al.”
BackgroundFeng, Y., Gan, X., Rong, X., & Han, Q. (2025) · Cancer Cell International · doi:10.1186/s12935-025-03946-0 · Cited by 19
“First, TET1 can regulate cellular plasticity and promote the acquisition of cellular plasticity in hepatocellular luminal cells during tissue injury or organ formation by activating the YAP/Hippo and ErbB/MAPK signalling pathways [43].”
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
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
Read, E., Peña‐Cearra, A., Coman, D., Jowett, G. M., Chung, M. W. H., Coales, I., Syntaka, S., Finlay, R. E., Tachó‐Piñot, R., van der Post, S., et al. (2023) · Mucosal Immunology · doi:10.1016/j.mucimm.2023.11.002 · Cited by 19
Research progress and application of liver organoids for disease modeling and regenerative therapy
Hu, Y., Geng, Q., Wang, L., Wang, Y., Huang, C., Fan, Z., & Kong, D. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-024-02455-3 · Cited by 21
“In 2019, Huch et al. [61] utilized cloning and long-term expansion of murine and human liver ductal cells to generate self-renewing bipotent organoids capable of differentiating into ductal and hepatocyte-like cells both in vitro and in vivo.”
BackgroundGuo, L., Hong, T., Lee, Y., Hu, X., Pan, G., Zhao, R., Yang, Y., Yang, J., Cai, X., Rivera, L., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01496-7 · Cited by 17
Iwasawa, K., & Takebe, T. (2021) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2021.06.007 · Cited by 19
Toxicoepigenetics and Environmental Health: Challenges and Opportunities
Svoboda, L. K., Perera, B. P. U., Morgan, R. K., Polemi, K. M., Pan, J., & Dolinoy, D. C. (2022) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.1c00445 · Cited by 17
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
“HpSCs can readily be expanded as bipotent stem cells into 3D organoids and differentiate into functional hepatocyte cells both in vitro and in vivo upon transplantation (93, 94).”
BackgroundDNA 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
Impact of hypoxia and AMPK on CFTR-mediated bicarbonate secretion in human cholangiocyte organoids
Roos, F. J. M., Bijvelds, M. J. C., Verstegen, M. M. A., Roest, H. P., Metselaar, H. J., Polak, W. G., de Jonge, H. R., IJzermans, J. N. M., & van der Laan, L. J. W. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00389.2020 · Cited by 14
Progress and perspective of organoid technology in cancer-related translational medicine
Lin, Y., Jiang, L., He, Q., Yuan, M., & Cao, J. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112869 · Cited by 18
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
“148 In a study, farnesoid X receptor (FXR) was demonstrated to be essential for liver regeneration driven by cholangio-cytes.”
Dompé, C., Janowicz, K., Hutchings, G., Moncrieff, L., Jankowski, M., Nawrocki, M. J., Józkowiak, M., Mozdziak, P. E., Petitte, J. N., Shibli, J. A., et al. (2020) · Cancers · doi:10.3390/cancers12041016 · Cited by 14
Zhang, Y., Lu, A., Zhuang, Z., Zhang, S., Liu, S., Chen, H., Yang, X., & Wang, Z. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s424737 · Cited by 14
Heterogeneous murine peribiliary glands orchestrate compartmentalized epithelial renewal
Singh, S., Lian, Q., Budiman, T., Taketo, M. M., Simons, B. D., & Gupta, V. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.10.004 · Cited by 14
Cell heterogeneity and fate bistability drive tissue patterning during intestinal regenerationPreprint
Schwayer, C., Barbiero, S., Brückner, D. B., Baader, C., Repina, N. A., Diaz, O. E., Meylan, L. C., Kalck, V., Suppinger, S., Yang, Q., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.14.632683 · Cited by 13
Cellular and Transcriptional Heterogeneity in the Intrahepatic Biliary Epithelium
Hrncir, H. R., & Gracz, A. D. (2022) · Gastro Hep Advances · doi:10.1016/j.gastha.2022.07.015 · Cited by 12
Platform-agnostic CellNet enables cross-study analysis of cell fate engineering protocols
Lo, E. K. W., Velazquez, J. J., Peng, D., Kwon, C., Ebrahimkhani, M. R., & Cahan, P. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.06.008 · Cited by 14
He, J., Cui, H., Shi, X., Jin, Q., Han, X., Han, T., Peng, J., Guo, S., Zhang, L., Zhao, Y., et al. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac055 · Cited by 13
“GSEA analysis indicated that HBOs showed the enrichment of cholangiocyte-regeneration regulation pathway ERBB signaling pathway [33] (Fig.”
Peng, Y., Wang, H., Huang, X., Liu, H., Xiao, J., Wang, C., Ma, L., Wang, X., & Cao, Z. (2023) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14979 · Cited by 11
NOTCH signalling – a core regulator of bile duct disease?
Lyons, A. M., & Boulter, L. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.050231 · Cited by 12
Application of Organoids in Carcinogenesis Modeling and Tumor Vaccination
Wang, Z., Zhao, S., Lin, X., Chen, G., Kang, J., Ma, Z., Wang, Y., Li, Z., Xiao, X., He, A., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.855996 · Cited by 13
“This work that was inspired by those epigenetic changes of organoids from normal to malignant cell transition was able to determine subsequent uncontrollable modification of genetic machinery, eventually leading to malignant occurrence and development (95, 98, 100).”
BackgroundSox9 inhibits Activin A to promote biliary maturation and branching morphogenesis
Hrncir, H. R., Goodloe, B., Bombin, S., Hogan, C. B., Jadi, O., & Gracz, A. D. (2025) · Nature Communications · doi:10.1038/s41467-025-56813-x · Cited by 10
Tian, X., Wang, Y., Lu, Y., Wu, B. Y., Chen, S., Du, J. C., Cai, W., & Xiao, Y. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05450-z · Cited by 11
“In addition, TET1 catalytic activity is required for cholangiocyte organoid formation and liver regeneration [40].”
BackgroundReches, G., Blondheim-Shraga, N., Carrette, F., Malka, A., Saleev, N., Gubbay, Y., Ertracht, O., Haviv, I., Bradley, L. M., Levine, F., et al. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00238-2 · Cited by 10
Female Reproductive Tract Organoids: Applications from Physiology to Pathology
Wang, X., Yang, D., & Peng, H. (2025) · Biomolecules · doi:10.3390/biom15070925 · Cited by 10
“Wnt signaling pathway agonists [108–110] Nicotinamide Inhibit cell differentiation [54,110–112] N-acetyl-L-Cysteine ROS inhibitors, with antioxidant effects [113] Noggin Regulate cell differentiation, proliferation, and apoptosis [35,111–114] Epithelial Growth Factor (EGF) Promote cell…”
From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease
Kunst, R. F., Niemeijer, M., van der Laan, L. J. W., Spee, B., & van de Graaf, S. F. J. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114173 · Cited by 9
Preclinical-to-clinical innovations in stem cell therapies for liver regeneration
Chawla, S., & Das, A. (2022) · Current Research in Translational Medicine · doi:10.1016/j.retram.2022.103365 · Cited by 10
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
“Moreover, flow cytometry analysis of BECs stained with EPCAM, a panBEC marker (Aloia et al., 2019; PepeMooney et al., 2019; PlanasPaz et al., 2019) and BODIPY confirmed that these”
BackgroundMethodInfluentialA narrative review of organoids for investigating organ aging: opportunities and challenges
Sun, X., Sun, F., Zhang, Y., Qu, J. T., Zhang, W., & Liu, G. (2023) · Journal of Bio-X Research · doi:10.1097/jbr.0000000000000139 · Cited by 8
Metadata
- Authors
- 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., Belenguer, G., Mort, R. L., Brand, A. H., Zernicka-Goetz, M., Forbes, S. J., Miska, E. A., & Huch, M.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- MRC Centre for Regenerative Medicine (GB)
- Lancaster University (GB)
- Corresponding author
- Huch, Meritxell
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-11
- Volume
- 21
- Issue
- 11
- Pages
- 1321-1333
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6940196
- OpenAlex
- W2986073722
- Cited by
- 160
- References
- 83
- Citations by year
- 2026: 6 · 2025: 26 · 2024: 21 · 2023: 22 · 2022: 42 · 2021: 24 · 2020: 18
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Lancaster EPrints (Lancaster University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Iris (University of Trento) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (104640/Z/14/Z, 104151/Z/14/Z, 092096/Z/10/Z, 105839, 104151, C6946/A14492, 103792/Z/14/Z, 105839/Z/14/Z, 104640, 092096, 103792)
- Cancer Research UK (A18583, C13474/A18583, C6946 /A14492, 092096, C6946, 18583, A14492)
- Royal Society (RP150061)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/R001162/1)
- Cambridge Trust
- National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/R001162/1)
- Darwin Trust of Edinburgh
- Horizon 2020 Framework Programme (MSCA-IF-2016, 668350)
- Medical Research Council (MR/P016839/1, MC_PC_12009, MR/K017047/1, MR/K50127X/1)
- Cancer Research UK Cambridge Institute, University of Cambridge (C6946/A14492)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- cholangiocytes, liver regeneration, liver organoids, epigenetic remodeling, TET1, DNA hydroxymethylation, cellular plasticity, stemness genes, hepatocyte differentiation, tissue damage
- MeSH terms
- Epigenome, Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Bile Ducts, DNA-Binding Proteins, Epithelial Cells, Female, Liver, Liver Regeneration, Male, Mice, Transgenic, Organoids, Proto-Oncogene Proteins, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, DNA Methylation, Gene Expression Profiling, Epigenesis, Genetic, Adaptor Proteins, Signal Transducing, Transcriptome, Primary Cell Culture
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