ArticleGastroenterology2014
Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish.
Article in Gastroenterology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 130 papers.
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Who cites it
130 citing papers in PubMed, 234 citations in OpenAlex.
- HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis.The Journal of clinical investigation · 2018Trial
- Loss of arap3 drives a cerebral cavernous malformation-like phenotype in zebrafish via Krit1 interaction and RhoA dysregulation.Development (Cambridge, England) · 2026Article
- TGF-β serves as a critical signaling determinant of liver progenitor cell activation and function.The Journal of clinical investigation · 2026Article
- Balancing Discovery and Caution: Regeneration in zebrafish toxicology.Current opinion in toxicology · 2026Article
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- CellCousin2: an optimized system for partial ablation and tracing of regenerative lineages.NPJ Regenerative medicine · 2026Article
- Massive hepatic necrosis-associated acute liver failure.eGastroenterology · 2026Review
- Liver Progenitor Cells: Cellular Origins, Plasticity, and Signaling Pathways in Liver Regeneration.Biology · 2025Review
- Triggering Mechanisms of Hepatocyte Repopulation during Liver Regeneration.Biomolecules & therapeutics · 2025Review
- Review
- Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish.Nature communications · 2025Article
- Khdrbs1 drives re-differentiation of bipotential progenitor cells by inhibiting p53 in zebrafish biliary-mediated liver regeneration.Development (Cambridge, England) · 2025Article
- Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics.Signal transduction and targeted therapy · 2025Review
- Gallbladder-derived retinoic acid signalling drives reconstruction of the damaged intrahepatic biliary ducts.Nature cell biology · 2025Article
- Mesenchymal stem cells lineage and their role in disease development.Molecular medicine (Cambridge, Mass.) · 2024Review
- mTORC1 mediates the expansion of hematopoietic stem and progenitor cells through ribosome biogenesis protein Urb2 in zebrafish.Stem cell reports · 2024Article
- Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications.Medical review (2021) · 2024Review
- Epidermal growth factor-like domain 7 drives brain lymphatic endothelial cell development through integrin αvβ3.Nature communications · 2024Article
- Meningeal lymphatic supporting cells govern the formation and maintenance of zebrafish mural lymphatic endothelial cells.Nature communications · 2024Article
- Article
70 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issuedCorrigendum.2025
Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsThe liver has high regenerative capacity, but it is not clear whether most biliary cells (particularly larger cholangiocytes) transdifferentiate into hepatocytes in regenerating liver. We investigated how this process might contribute to liver regeneration in zebrafish.
methodsZebrafish transgenic lines were generated using the standard I-SceI meganuclease transgenesis technique. Hepatocytes of the Tg(lfabp:mCherry-NTR)(cq2) animals were ablated by the administration of metronidazole. We investigated transdifferentiation of biliary cells to hepatocytes and expression of markers using whole mount antibody staining, fluorescent in situ hybridization, and Cre/loxP-based genetic lineage tracing analyses. The role of biliary cells in hepatocyte regeneration was explored using zebrafish larvae with defects in biliary cell development.
resultsAfter extreme loss of hepatocytes, nearly all the biliary cells steadily lost their tubular morphology, proliferated, and expressed hepatocyte-specific markers. Cre/loxP-based inducible lineage tracing showed that new hepatocytes mainly arose from transdifferentiation of biliary cells; this process required Notch signaling and, in turn, activation of Sox9b in cholangiocytes. Activation of early endoderm and hepatoblast markers in most of the cholangiocytes indicated that biliary transdifferentiation includes a step of dedifferentiation into a bipotential intermediate. Defects in development of biliary cells impaired hepatocyte regeneration.
conclusionsUsing our zebrafish liver regeneration model, we found that biliary cells can transdifferentiate into hepatocytes and are the major contributors to hepatocyte regeneration after extreme hepatocyte loss.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.