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 pathways, YAP activity is able to be amplified robustly to ensure a timely adjustment during liver injury and regeneration.
“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]
The Results section (page not available in our copy) shows that TET1-mediated epigenetic regulation affects YAP/Hippo pathway components during the response to liver damage; the Discussion says this contributes to ductal-cell regeneration. The paper does not establish that coordination among multiple epigenetic pathways robustly amplifies YAP activity or ensures a timely adjustment. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPooling different cells and/or organoids for bulk analysis can lead to inaccurate results.
“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]
The Results section on organoid initiation describes RNA-sequencing of ductal cells at several time points, but does not say that pooling different cells or organoids makes bulk analysis inaccurate. A search for pooling, bulk analysis, and heterogeneity found no passage addressing that concern in our copy. (LLM, conf=0.72)
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Self-citationTET (Ten-eleven translocation) family proteins: structure, biological functions and applications
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“75 Epigenetic programming by catalytic-dependent TET1 is implicated in liver regeneration 76 and remyelination in mouse brain.”
BackgroundIntegrating organoids and organ-on-a-chip devices
Zhao, Y., Landau, S., Okhovatian, S., Liu, C., Lu, R. X. Z., Lai, B. F. L., Wu, Q., Kieda, J., Cheung, K., Rajasekar, S., et al. (2024) · Nature Reviews Bioengineering · doi:10.1038/s44222-024-00207-z · Cited by 206 · see citing works
“Moreover, differentiated cells, such as cholangiocytes, can acquire cellular plasticity and clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells 11 .”
A Chemically Defined Hydrogel for Human Liver Organoid Culture
Ye, S., Boeter, J. W. B., Mihajlovic, M., van Steenbeek, F. G., van Wolferen, M. E., Oosterhoff, L. A., Marsee, A., Caiazzo, M., van der Laan, L. J. W., Penning, L. C., et al. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202000893 · Cited by 165 · see citing works
Organoids to model liver disease
Nuciforo, S., & Heim, M. H. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2020.100198 · Cited by 164 · see citing works
Control of stem cell renewal and fate by YAP and TAZ
Driskill, J. H., & Pan, D. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00644-5 · Cited by 165 · see citing works
Epithelial Plasticity during Liver Injury and Regeneration
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Self-citationHepatic Stellate Cell Regulation of Liver Regeneration and Repair
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“Aloia et al.(44) compared the transcriptional profile of cholangiocyte organoids and cholangiocytes isolated from livers of mice given a 3,5- diethoxycarbonyl-1,4-dihydrocollidine supplemented diet.”
BackgroundLiver 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
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NOTCH-YAP1/TEAD-DNMT1 Axis Drives Hepatocyte Reprogramming Into Intrahepatic Cholangiocarcinoma
Hu, S., Molina, L. M., Tao, J., Liu, S., Hassan, M., Singh, S., Poddar, M., Bell, A. W., Sia, D., Oertel, M., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2022.05.007 · Cited by 103 · see citing works
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Chembazhi, U. V., Bangru, S., Hernaez, M., & Kalsotra, A. (2021) · Genome Research · doi:10.1101/gr.267013.120 · Cited by 102 · see citing works
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Hallmarks of stemness in mammalian tissues
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“Using this model system, we have shown that liver ductal organoids recapitulate many aspects of liver regeneration in a dish (Aloia et al., 2019).”
Self-citationMarakulina, D., Vorontsov, I. E., Kulakovskiy, I. V., Lennartsson, A., Drabløs, F., & Medvedeva, Y. A. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac989 · Cited by 78 · see citing works
Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma
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“Epigenetic programming mediated by the catalytic activity of TET1 has been implicated in liver regeneration [143] and in remyelination within the mouse brain [144,145].”
BackgroundHuman liver organoids: From generation to applications
Afonso, M. B., Marques, V., van Mil, S. W. C., & Rodrigues, C. M. P. (2024) · Hepatology · doi:10.1097/hep.0000000000000343 · Cited by 61 · see citing works
“[10] These mouse liver organoids turned out to originate from adult cholangiocytes that, by epigenetic reprogramming, adopt a progenitor cell state [11,12] and are therefore classified as intrahepatic cholangiocyte organoids (ICOs).”
BackgroundContext-dependent roles of YAP/TAZ in stem cell fates and cancer
LeBlanc, L., Ramirez, N., & Kim, J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03781-2 · Cited by 63 · see citing works
“For example, an organoid model of severe liver damage reveals that the activity of YAP is essential for TET1, a DNA demethylase implicated in reprogramming, to epigenetically reset ductal cells, allowing them to differentiate into cholangiocytes and hepatocytes [88].”
BackgroundJia, Y., Li, L., Lin, Y.-H., Gopal, P., Shen, S., Zhou, K., Yu, X., Sharma, T., Zhang, Y., Siegwart, D. J., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.01.001 · Cited by 59 · see citing works
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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
Liver Organoids: Formation Strategies and Biomedical Applications
Zhu, X., Zhang, B., He, Y., & Bao, J. (2021) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-021-00357-w · Cited by 55 · see citing works
Hippo-Yap/Taz signalling in zebrafish regeneration
Riley, S. E., Feng, Y., & Hansen, C. G. (2022) · npj Regenerative Medicine · doi:10.1038/s41536-022-00209-8 · Cited by 52 · see citing works
From organoids to organoids-on-a-chip: Current applications and challenges in biomedical research
Liu, K., Chen, X., Fan, Z., Ren, F., Liu, J., & Hu, B. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003535 · Cited by 56 · see citing works
“[11,12] The pioneering report on organoids described human adult stem cell-derived gut organoids featuring crypt-villus structures similar to the epithelium of native intestinal tissues.”
Organoids and regenerative hepatology
Jalan‐Sakrikar, N., Brevini, T., Huebert, R. C., & Sampaziotis, F. (2022) · Hepatology · doi:10.1002/hep.32583 · Cited by 50 · see citing works
“It is believed that the disease niche, which is, to some extent, recapitulated by canonical Wnt signaling in vitro, causes epigenetic remodeling of cholangiocytes, unlocking their stem cell potential.[76] Primary cholangiocytes grown in conditions based on noncanonical Wnt signaling give rise to mature primary cholang…”
BackgroundSo, 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
The Hippo pathway: Organ size control and beyond
Guo, P., Wan, S., & Guan, K. (2024) · Pharmacological Reviews · doi:10.1016/j.pharmr.2024.100031 · Cited by 45 · see citing works
Recent advances in organoid engineering: A comprehensive review
Unagolla, J. M., & Jayasuriya, A. C. (2022) · Applied Materials Today · doi:10.1016/j.apmt.2022.101582 · Cited by 44 · see citing works
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Mouse liver assembloids model periportal architecture and biliary fibrosis
Dowbaj, A. M., Sljukic, A., Niksic, A., Landerer, C., Delpierre, J., Yang, H., Lahree, A., Kühn, A. C., Beers, D., Byrne, H. M., et al. (2025) · Nature · doi:10.1038/s41586-025-09183-9 · Cited by 40 · see citing works
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Self-citationRoos, F. J. M., Wu, H., Willemse, J., Lieshout, R., Albarinos, L. A. M., Kan, Y., Poley, J., Bruno, M. J., de Jonge, J., Bártfai, R., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.566 · Cited by 40 · see citing works
Microencapsulation-based cell therapies
Marikar, S. N., El‐Osta, A., Johnston, A. P. R., Such, G. K., & Al‐Hasani, K. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04369-0 · Cited by 41 · see citing works
Central role for cholangiocyte pathobiology in cholestatic liver diseases
Jalan-Sakrikar, N., Guicciardi, M. E., O’Hara, S. P., Azad, A., LaRusso, N. F., Gores, G. J., & Huebert, R. C. (2025) · Hepatology · doi:10.1097/hep.0000000000001093 · Cited by 38 · see citing works
Tang, J. L. Y., Hakes, A. E., Krautz, R., Suzuki, T., Contreras, E. G., Fox, P. M., & Brand, A. H. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.04.008 · Cited by 39 · see citing works
“NanoDam can be readily adapted for use in other organisms to facilitate easier in vivo profiling experiments, as we have demonstrated previously for TaDa (Cheetham et al., 2018; Aloia et al., 2019).”
BackgroundSelf-citationWillemse, J., Roos, F. J. M., Voogt, I. J., Schurink, I. J., Bijvelds, M., de Jonge, H. R., van der Laan, L. J. W., de Jonge, J., & Verstegen, M. M. A. (2021) · Biotechnology and Bioengineering · doi:10.1002/bit.27613 · Cited by 35 · see citing works
“Human LGR5 biliary organoids are an interesting source of functional biliary cells, as organoids offer long‐term stable in vitro expansion of cholangiocytes (Aloia et al., 2019; Huch et al., 2015).”
BackgroundInfluentialGelatin-Based Hybrid Hydrogels as Matrices for Organoid Culture
Carpentier, N., Ye, S., Delemarre, M. D., der Meeren, L. V., Skirtach, A. G., van der Laan, L. J. W., Schneeberger, K., Spee, B., Dubruel, P., & Vlierberghe, S. V. (2024) · Biomacromolecules · doi:10.1021/acs.biomac.2c01496 · Cited by 34 · see citing works
Chromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Zhang, C., Macchi, F., Magnani, E., & Sadler, K. C. (2021) · Nature Communications · doi:10.1038/s41467-021-24466-1 · Cited by 31 · see citing works
Distinct 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
Self-organization of organoids from endoderm-derived cells
Lewis, A. C., Keshara, R., Kim, Y. H., & Grapin‐Botton, A. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-02010-w · Cited by 30 · see citing works
“[67] revealed transient transcriptional and epigenetic remodeling of differentiated ductal cells in response to”
BackgroundTao, S., Huang, J., Li, Z.-X., Zhan, S., & Guo, S. (2021) · iScience · doi:10.1016/j.isci.2021.102200 · Cited by 29 · see citing works
Role of Immune Cells in Biliary Repair
Lan, T., Qian, S., Tang, C., & Gao, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.866040 · Cited by 29 · see citing works
“Such lineage specification is modulated by an intricate signaling network, including the Notch (31), Wnt-bcatenin (31–34), and Hippo-Yes-associated protein (YAP) signaling pathways (35, 36).”
BackgroundThe promise of human organoids in the digestive system
Funata, M., Nio, Y., Erion, D. M., Thompson, W. L., & Takebe, T. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-00661-3 · Cited by 27 · 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
Human assembloids recapitulate periportal liver tissue in vitro
Yuan, L., Dawka, S., Kim, Y., Liebert, A., Rost, F., Arnes‐Benito, R., Baenke, F., Götz, C., Tsang, D., Schuhmann, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09884-1 · Cited by 26 · see citing works
“We 19,20 and others 21,22 have demonstrated that these models enable the study of mouse liver regeneration in vitro.”
Self-citationEpigenetic 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
Self-citationYin, Y., Kong, D., He, K., & Xia, Q. (2021) · Liver International · doi:10.1111/liv.15094 · Cited by 26 · see citing works
Shi, S., Roest, H. P., van den Bosch, T. P. P., Bijvelds, M. J. C., Boehnert, M. U., de Jonge, J., Dekker, S. O., de Vries, A. A. F., de Jonge, H. R., Verstegen, M. M. A., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2022.104431 · Cited by 26 · see citing works
Liver organoids: updates on generation strategies and biomedical applications
Liu, S., Cheng, C., Zhu, L., Zhao, T., Wang, Z., Yi, X., Yan, F., Wang, X., Li, C., Cui, T., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03865-3 · Cited by 26 · see citing works
“Although early reports on the establishment of organoid systems indicated that organoids are exclusively derived from stem cells [9], it is now clear that organoids can also be initiated from differentiated cells, such as cholangiocytes [10].”
BackgroundRoos, F. J. M., Verstegen, M. M. A., Albarinos, L. M., Roest, H. P., Poley, J., Tetteroo, G. W. M., IJzermans, J. N. M., & van der Laan, L. J. W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.630492 · Cited by 25 · see citing works
“Cholangiocytes organoids, either initiated from tissue or bile in both culture conditions, are most likely risen from primary cholangiocytes (Sampaziotis et al., 2017; Hu et al., 2018; Aloia et al., 2019; Planas-Paz et al., 2019).”
BackgroundTargeting epigenetic alterations in cancer stem cells
Verona, F., Pantina, V. D., Modica, C., Lo Iacono, M., D’Accardo, C., Porcelli, G., Cricchio, D., Turdo, A., Gaggianesi, M., Franco, S. D., et al. (2022) · Frontiers in Molecular Medicine · doi:10.3389/fmmed.2022.1011882 · Cited by 26 · see citing works
“As reported in the literature, differentiated hepatocytes, in response to tissue damage undergo a rewiring of genomic methylome/hydroxymethylome landscapes reverting lineage-committed and contributing to the regeneration of liver parenchyma (Aloia et al., 2019).”
Bioengineered Tubular Biliary Organoids
Elci, B. S., Nikolaev, M., Rezakhani, S., & Lütolf, M. P. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302912 · 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
“…reduces the HPC replicative potential and promotes an in fl ammatory phenotype. activated mainly in the portal region and induce activation of quiescent biliary epithelial cells or metaplasia of hepatocytes into proliferating progenitors, required for DR-dependent liver regeneration [62, 65, 147].”
Genetically modified organoids for tissue engineering and regenerative medicine
Zhang, Q., Jin, H., Zhu, D., Chen, Y., Fu, M., Lu, S., Qiu, Y., Zhou, G., Yang, G., & Jiang, Z. (2024) · Advances in Colloid and Interface Science · doi:10.1016/j.cis.2024.103337 · Cited by 21 · see citing works
Advances in liver and pancreas organoids: how far we have come and where we go next
Sljukic, A., Jenkinson, J. G., Niksic, A., Prior, N., & Huch, M. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01116-1 · Cited by 23 · see citing works
“These organoids are not only genetically stable but can also largely maintain the epigenetic profile of the in vivo cells 64,65 and show a reduced tumorigenic potential compared with PSC-derived organoids 66 .”
Self-citationWaddell, S. H., Yao, Y., Olaizola, P., Walker, A., Jarman, E. J., Gournopanos, K., Grãdinaru, A., Christodoulou, E., Gautier, P. E., Boerrigter, M. M., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abq5930 · Cited by 19 · see citing works
New developments and applications of human organoids
Andersson-Rolf, A., & Clevers, H. C. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-00974-0 · Cited by 22 · see citing works
“Studies utilizing mouse TSC-derived organoids have identified YAP signalling as a central player in the regenerative response of both the intestine 192 and the liver 193 .”
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
Chen, J., Ma, S., Yang, H., Liang, X., Yao, H., Guo, B., Chen, D., Jiang, J., Shi, D., Xin, J., et al. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.03.012 · Cited by 20 · 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
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 · see citing works
“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 18 · see citing works
“The Huch group [31] found that TET1-mediated hydroxymethylation allows differentiated ductal cells to initiate organoids and activate the regenerative program through the transcriptional regulation of stem-cell genes and regenerative pathways, including YAP–Hippo signaling; these results [31] argued in favor of the re…”
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 · see citing works
“…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 · see citing works
“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 17 · see citing works
“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 · 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
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 17 · see citing works
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 18 · see citing works
“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 · see citing works
Iwasawa, K., & Takebe, T. (2021) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2021.06.007 · Cited by 16 · see citing works
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 16 · see citing works
Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases
Safarikia, S., Carpino, G., Overi, D., Cardinale, V., Venere, R., Franchitto, A., Onori, P., Alvaro, D., & Gaudio, E. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00479 · Cited by 16 · see citing works
“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 · see citing works
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 15 · see citing works
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 16 · see citing works
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“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 · see citing works
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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 · see citing works
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 · see citing works
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 · see citing works
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 12 · see citing works
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“GSEA analysis indicated that HBOs showed the enrichment of cholangiocyte-regeneration regulation pathway ERBB signaling pathway [33] (Fig.”
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NOTCH signalling – a core regulator of bile duct disease?
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Application of Organoids in Carcinogenesis Modeling and Tumor Vaccination
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“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
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“In addition, TET1 catalytic activity is required for cholangiocyte organoid formation and liver regeneration [40].”
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Female Reproductive Tract Organoids: Applications from Physiology to Pathology
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“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
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Preclinical-to-clinical innovations in stem cell therapies for liver regeneration
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Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
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“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”
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- 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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