Spatial gene regulatory networks driving cell state transitions during human liver disease
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.
Authors
- Nicoletta Bobola (ORCID: https://orcid.org/0000-0002-7103-4932)
- Neil A. Hanley (ORCID: https://orcid.org/0000-0003-3234-4038)
- Ajith K. Siriwardena (ORCID: https://orcid.org/0000-0001-8004-0560)
- Nigel L. Hammond (ORCID: https://orcid.org/0000-0003-3086-5243)
- Huw Purssell (ORCID: https://orcid.org/0000-0003-1647-9629)
- Syed Murtuza Baker (ORCID: https://orcid.org/0000-0002-6633-333X)
- Magnus Rattray (ORCID: https://orcid.org/0000-0001-8196-5565)
- Andrew D Sharrocks (ORCID: https://orcid.org/0000-0001-7395-9552)
- Leoma Bere (ORCID: https://orcid.org/0000-0001-5421-2154)
- Mike J. Dixon (ORCID: https://orcid.org/0000-0001-9546-8607)
- Harry Spiers (ORCID: https://orcid.org/0000-0001-7308-2711)
- Elliot Jokl (ORCID: https://orcid.org/0000-0003-2556-3777)
- Karen Piper Hanley (ORCID: https://orcid.org/0000-0001-9473-9647)
- Kevin N. Couper (ORCID: https://orcid.org/0000-0003-4659-8960)
- Kara Simpson (ORCID: https://orcid.org/0000-0001-7950-5703)
- Rosa Sánchez‐Alvarez (ORCID: https://orcid.org/0000-0002-1138-2011)
- Sokratia Georgaka (ORCID: https://orcid.org/0000-0002-0078-8083)
- Michael Haley (ORCID: https://orcid.org/0000-0003-2485-8485)
- Varinder Singh Athwal (ORCID: https://orcid.org/0000-0002-1684-721X)
- Adam P. Jones (ORCID: https://orcid.org/0000-0003-2321-5584)
- Ali Al-Anbaki
Institutions
- University Hospitals Birmingham NHS Foundation Trust (GB)
- University of Cambridge (GB)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
- Manchester University NHS Foundation Trust (GB)
- University of Birmingham (GB)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1038/s44321-025-00230-6
- Citations
- 2
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.64
Funders
- Wellcome Trust
- Medical Research Council
- Biotechnology and Biological Sciences Research Council