A spatiotemporal atlas of cholestatic injury and repair in mice

Nat Genet. 2024 May;56(5):938-952. doi: 10.1038/s41588-024-01687-w. Epub 2024 Apr 16.


Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFβ in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bile Ducts / metabolism
  • Cell Proliferation / genetics
  • Cholestasis* / genetics
  • Cholestasis* / metabolism
  • Cholestasis* / pathology
  • Disease Models, Animal
  • Hepatocytes* / metabolism
  • Liver / injuries
  • Liver / metabolism
  • Liver / pathology
  • Liver Regeneration / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Spatio-Temporal Analysis
  • Transcriptome
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism