Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish
Abstract 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....
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| Format: | Article |
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60334-y |
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| author | Sema Elif Eski Jiarui Mi Macarena Pozo-Morales Gabriel Garnik Hovhannisyan Camille Perazzolo Rita Manco Imane Ez-Zammoury Dev Barbhaya Anne Lefort Frédérick Libert Federico Marini Esteban N. Gurzov Olov Andersson Sumeet Pal Singh |
| author_facet | Sema Elif Eski Jiarui Mi Macarena Pozo-Morales Gabriel Garnik Hovhannisyan Camille Perazzolo Rita Manco Imane Ez-Zammoury Dev Barbhaya Anne Lefort Frédérick Libert Federico Marini Esteban N. Gurzov Olov Andersson Sumeet Pal Singh |
| author_sort | Sema Elif Eski |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-6fc06ebf2c1e488fadd97f102767d744 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6fc06ebf2c1e488fadd97f102767d7442025-08-20T02:05:38ZengNature PortfolioNature Communications2041-17232025-06-0116111810.1038/s41467-025-60334-yCholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafishSema Elif Eski0Jiarui Mi1Macarena Pozo-Morales2Gabriel Garnik Hovhannisyan3Camille Perazzolo4Rita Manco5Imane Ez-Zammoury6Dev Barbhaya7Anne Lefort8Frédérick Libert9Federico Marini10Esteban N. Gurzov11Olov Andersson12Sumeet Pal Singh13Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de BruxellesDepartment of Cell and Molecular Biology, Karolinska InstitutetLaboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de Bruxelles, AnderlechtLaboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de BruxellesLaboratory of Hepato-gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de LouvainFaculty of Pharmacy and Biomedical Sciences, Université Catholique de LouvainIndian Institute of Technology Kanpur (IIT-Kanpur)Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de BruxellesLaboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de BruxellesInstitute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University MainzSignal Transduction and Metabolism Laboratory, Université libre de Bruxelles, AnderlechtDepartment of Cell and Molecular Biology, Karolinska InstitutetLaboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de BruxellesAbstract 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.https://doi.org/10.1038/s41467-025-60334-y |
| spellingShingle | Sema Elif Eski Jiarui Mi Macarena Pozo-Morales Gabriel Garnik Hovhannisyan Camille Perazzolo Rita Manco Imane Ez-Zammoury Dev Barbhaya Anne Lefort Frédérick Libert Federico Marini Esteban N. Gurzov Olov Andersson Sumeet Pal Singh Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish Nature Communications |
| title | Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish |
| title_full | Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish |
| title_fullStr | Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish |
| title_full_unstemmed | Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish |
| title_short | Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish |
| title_sort | cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish |
| url | https://doi.org/10.1038/s41467-025-60334-y |
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