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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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BackgroundIntegrating organoids and organ-on-a-chip devices
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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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