Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish
The liver's regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.
Authors
- Sema Elif Eski (ORCID: https://orcid.org/0000-0002-4757-8614)
- Anne Lefort
- Rita Manco (ORCID: https://orcid.org/0000-0003-0857-6322)
- Camille Perazzolo
- Esteban N. Gurzov (ORCID: https://orcid.org/0000-0003-4642-0273)
- Macarena Pozo‐Morales (ORCID: https://orcid.org/0000-0003-2654-1895)
- Olov Andersson (ORCID: https://orcid.org/0000-0001-6715-781X)
- Dev Barbhaya (ORCID: https://orcid.org/0000-0003-3956-4906)
- Jiarui Mi (ORCID: https://orcid.org/0000-0001-6498-3817)
- Sumeet Pal Singh (ORCID: https://orcid.org/0000-0002-5154-3318)
- Fédérico Marini (ORCID: https://orcid.org/0000-0003-3252-7758)
- Gayane Hovhannisyan
- Frédérick Libert
- Imane Ez-Zammoury
Institutions
- Uppsala University (SE)
- Université Libre de Bruxelles (BE)
- Johannes Gutenberg University Mainz (DE)
- Shiv Nadar University (IN)
- Sir Run Run Shaw Hospital (CN)
- Karolinska Institutet (SE)
- Spanish National Cancer Research Centre (ES)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Zhejiang University (CN)
- Indian Institute of Technology Kanpur (IN)
- UCLouvain (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1038/s41467-025-60334-y
- Citations
- 8
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 16.05
Funders
- University of Pittsburgh
- New York University Abu Dhabi
- Department of Biotechnology, Ministry of Science and Technology, India
- Deutsche Forschungsgemeinschaft
- Fonds De La Recherche Scientifique - FNRS
- Zentrum für Regenerative Therapien Dresden
- Université Libre de Bruxelles
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture