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<p>Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis. Through multi-modal data integration, we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory between hepatocytes and cholangiocytes associated with disease remodelling. We identify pro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach provides a spatial atlas of gene regulation and defines molecular signatures associated with liver disease for targeted therapeutics or as early diagnostic markers of progressive liver disease.</p>

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Spatial gene regulatory networks driving cell state transitions during human liver disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月25日

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  • Nigel L Hammond,
  • Syed Murtuza Baker,
  • Sokratia Georgaka,
  • Ali Al-Anbaki,
  • Elliot Jokl,
  • Kara Simpson,
  • Rosa Sanchez-Alvarez,
  • Varinder S Athwal,
  • Huw Purssell,
  • Ajith K Siriwardena,
  • Harry V M Spiers,
  • Mike J Dixon,
  • Leoma D Bere,
  • Adam P Jones,
  • Michael J Haley,
  • Kevin N Couper,
  • Nicoletta Bobola,
  • Andrew D Sharrocks,
  • Neil A Hanley,
  • Magnus Rattray,
  • Karen Piper Hanley

摘要

Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis. Through multi-modal data integration, we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory between hepatocytes and cholangiocytes associated with disease remodelling. We identify pro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach provides a spatial atlas of gene regulation and defines molecular signatures associated with liver disease for targeted therapeutics or as early diagnostic markers of progressive liver disease.