Eski Sema Elif, Mi Jiarui, Pozo-Morales Macarena, Hovhannisyan Gabriel Garnik, Perazzolo Camille, Manco Rita, Ez-Zammoury Imane, Barbhaya Dev, Lefort Anne, Libert Frédérick, Marini Federico, Gurzov Esteban N, Andersson Olov, Singh Sumeet Pal
Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de Bruxelles, Brussels, Belgium.
Department of Cell and Molecular Biology, Karolinska Institutet, 17177, Stockholm, Sweden.
Nat Commun. 2025 Jun 6;16(1):5260. doi: 10.1038/s41467-025-60334-y.
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.
肝脏的再生能力取决于损伤程度。轻微损伤通过肝细胞自我复制修复，而严重损伤则会促使胆管细胞参与肝细胞的恢复。这种模式在成年动物中已有充分记录，但在快速生长过程中研究较少。我们在斑马鱼中设计了两种部分肝损伤模型，并在生长高峰期对其进行研究：1）部分消融，杀死一半的肝细胞；2）部分肝切除术，切除半个肝叶。在这两种损伤中，新生肝细胞与现有的肝细胞一同出现。单细胞转录组学以及通过基因组编辑产生的Cre驱动系进行的谱系追踪将胆管细胞确定为新生肝细胞的来源。我们进一步确定，生长中动物未受伤肝脏中活跃的mTORC1信号是胆管细胞增强可塑性的调节因子。我们的研究表明，胆管细胞向肝细胞的转分化是快速生长期间肝脏再生的主要机制。
