Spatial gene regulatory networks driving cell state transitions during human liver disease
Abstract
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.
Author
Hammond, Nigel L
Murtuza Baker, Syed
Georgaka, Sokratia
Al-Anbaki, Ali
Jokl, Elliot
Simpson, Kara
Sanchez-Alvarez, Rosa
Athwal, Varinder S
Purssell, Huw
Siriwardena, Ajith K
Spiers, Harry V M
Dixon, Mike J
Bere, Leoma D
Jones, Adam P
Haley, Michael J
Couper, Kevin N
Bobola, Nicoletta
Sharrocks, Andrew D
Hanley, Neil A
Rattray, Magnus
Piper Hanley, Karen
Murtuza Baker, Syed
Georgaka, Sokratia
Al-Anbaki, Ali
Jokl, Elliot
Simpson, Kara
Sanchez-Alvarez, Rosa
Athwal, Varinder S
Purssell, Huw
Siriwardena, Ajith K
Spiers, Harry V M
Dixon, Mike J
Bere, Leoma D
Jones, Adam P
Haley, Michael J
Couper, Kevin N
Bobola, Nicoletta
Sharrocks, Andrew D
Hanley, Neil A
Rattray, Magnus
Piper Hanley, Karen
Date
2025-04-25
Type
Article
Subject
Liver cirrhosis, Liver diseases, Cells
Collections
Citation
Hammond NL, Murtuza Baker S, Georgaka S, Al-Anbaki A, Jokl E, Simpson K, Sanchez-Alvarez R, Athwal VS, Purssell H, Siriwardena AK, Spiers HVM, Dixon MJ, Bere LD, Jones AP, Haley MJ, Couper KN, Bobola N, Sharrocks AD, Hanley NA, Rattray M, Piper Hanley K. Spatial gene regulatory networks driving cell state transitions during human liver disease. EMBO Mol Med. 2025 Jun;17(6):1452-1474. doi: 10.1038/s44321-025-00230-6. Epub 2025 Apr 25.
Journal / Source Title
EMBO Molecular Medicine
DOI
10.1038/s44321-025-00230-6
PMID
40281306
Publisher
EMBO Press
Publisher’s URL
https://www.embopress.org/journal/17574684