Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish

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 and Sumeet Pal Singh ()
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Sema Elif Eski: Université libre de Bruxelles
Jiarui Mi: Karolinska Institutet
Macarena Pozo-Morales: Université libre de Bruxelles
Gabriel Garnik Hovhannisyan: Anderlecht
Camille Perazzolo: Université libre de Bruxelles
Rita Manco: Université Catholique de Louvain
Imane Ez-Zammoury: Université Catholique de Louvain
Dev Barbhaya: Indian Institute of Technology Kanpur (IIT-Kanpur)
Anne Lefort: Université libre de Bruxelles
Frédérick Libert: Université libre de Bruxelles
Federico Marini: University Medical Center of the Johannes Gutenberg University Mainz
Esteban N. Gurzov: Anderlecht
Olov Andersson: Karolinska Institutet
Sumeet Pal Singh: Université libre de Bruxelles

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60334-y

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