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bioRxiv · 10.1101/2025.03.15.643421

Spatial single-cell interactome and niche-specific molecular signatures in alcohol-related liver disease

Petrenko, O.·Sorz-Nechay, T.·Bilban, M.·Derdak, S.·Van Melkebeke, L.·Huang, W.·Verbeek, J.·van der Merwe, S.·Hofer, B. S.·Simbrunner, B.·Reiberger, T.·Hendrikx, T.
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Abstract

Alcohol-related liver disease (ALD) remains a major global health burden with limited therapeutic options due to an incomplete understanding of its underlying molecular mechanisms and cellular crosstalk. Here, we applied ultra-high resolution (on 2 {micro}m spots) spatial transcriptomics to a cirrhotic liver tissue obtained from an end-stage ALD patient, analyzing >265,000 spatially resolved cells with further validation on single-cell and single-nuclei datasets from patients with ALD cirrhosis. Our analysis delineated distinct cellular sub-populations and molecular landscapes across fibrotic, vascular, and parenchymal niches of ALD cirrhosis. We identified robust zonation of hepatocytes, hepatic stellate cells, and diverse immune subpopulations, including enrichment of pro-inflammatory T cells and dendritic cells in the fibrotic niche and MARCO+ tissue-resident macrophages localizing mostly in parenchymal areas. Analysis of spatial metrics assigned expression of WNT4, RCAN3, PPIAL4G, PLA2G5, and SLC6A9 to the fibrotic environment in ALD. Differential expression and ligand-receptor interactome analyses revealed niche-specific signaling, with marked CCL19-CCR7 activity in fibrotic regions and DLL4-NOTCH3 crosstalk in vascular compartments. Notably, WNT4+ fibroblasts emerged as key mediators of extracellular matrix remodeling and chemoattraction, particularly via CCL19-mediated signaling towards CD8+ T cells, which was validated on single-cell resolution within the ALD cirrhotic liver in external datasets. These spatial and single-cell findings highlight novel potential therapeutic targets for patients with ALD cirrhosis.

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Petrenko, O., Sorz-Nechay, T., Bilban, M., Derdak, S., Van Melkebeke, L., Huang, W., Verbeek, J., van der Merwe, S., Hofer, B. S., Simbrunner, B., Reiberger, T., Hendrikx, T.. 2025-03-17. Spatial single-cell interactome and niche-specific molecular signatures in alcohol-related liver disease. https://doi.org/10.1101/2025.03.15.643421

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