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LEVERAGING SPATIAL MULTI-OMICS TO UNCOVER THE ROLE OF DUCTULAR REACTION IN THE PROGRESSION OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE

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LEVERAGING SPATIAL MULTI-OMICS TO UNCOVER THE ROLE OF DUCTULAR REACTION IN THE PROGRESSION OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE

Dania El Abyad 1, Markus Bösch 1, Ramy Younes 2, Simon Cockell 3, Jeremy Palmer 3, Michele Vacca 4, Michael Allison 5, Vlad Ratziu 6, Jörn Schattenberg 7, Ann K. Daly 3, Elisabetta Bugianesi 8, Dina Tiniakos 9, Tania Roskams 1, Quentin Anstee 10, Olivier Govaere 11

Affiliations

1 KU Leuven, Leuven, Belgium

2 Newcastle University, Newcastle Upon Tyne, United Kingdom|||University of Turin, Turin, Italy|||Boehringer Ingelheim International, Ingelheim, Germany

3 Newcastle University, Newcastle Upon Tyne, United Kingdom

4 Wellcome-MRC Institute of Metabolic Science, Bari, Italy

5 Cambridge University NHS Foundation Trust, Cambridge, United Kingdom

6 Sorbonne University, Paris, France

7 Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Mainz, Germany

8 AOU Città della Salute e della Scienza University of Torino, Torino, Italy, Torino, Italy

9 Newcastle University, Newcastle Upon Tyne, United Kingdom|||National & Kapodistrian University of Athens, Athens, Greece

10 Newcastle University, Newcastle, United Kingdom

11 KU Leuven, Leuven, Belgium|||Newcastle University, Newcastle Upon Tyne, United Kingdom

Summary

AI Generated

Multi-omics spatial profiling identified pro-inflammatory hepatic progenitor cell signatures that predict fibrosis progression in MASLD patients.

In a dual biopsy cohort, hepatic progenitor cell presence in the parenchyma at baseline was significantly associated with progression of at least 1 fibrosis stage and predicted fibrosis progression in a binary logistic regression model.
High-throughput transcriptomics of the hepatic progenitor cell niche identified 3,282 differentially expressed genes enriched in pro-inflammatory cytokines (CXCL6, CCL19, CCL2, CCL5, CCL21, SPP1), inflammatory cell markers (CCR2, CD48, CD8a, CD96, CXCR3, S100A4), and antigen presenting genes.
Spatial transcriptomics uncovered distinct ductular reaction subsets: SPP1+CCL2- cells localised predominantly in the parenchyma and peri-portal region, while CCL2+SPP1- cells were confined mainly to the portal tract.
The hepatic progenitor cell gene signature stratified 206 MASLD biopsies into clusters characterised by steatohepatitis, high disease activity, fibrosis and elevated AST levels.
Spatial proteomics identified CD48 and HLA-DR-expressing macrophages as key immune cells of the hepatic progenitor cell niche, with neighbourhood analysis highlighting antigen-presenting cells and IGHA1+IGHG1+ plasma cells in close proximity to ductular reaction.

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease estimated to affect 38% of the global adult population. Activation of hepatic progenitor cells (HPCs) and concurrent proliferation of reactive bile ducts (collectively referred to as ductular reaction) have been associated with advanced MASLD, liver fibrosis, and damage, yet their exact role during disease progression remains unclear.

Aims & Methods

This study aimed to investigate the prognostic and biological relevance of ductular reaction in the progression of MASLD by using a multi-omics approach. In this study, a total of 251 patient samples were included. Spatially resolved multi-omics techniques were implemented to characterise the HPC niche in advanced MASLD using laser microdissection combined with high-throughput RNA sequencing (RNA-seq), nanoString CosMx molecular profiling, followed by Lunaphore COMET proteome multiplexing at single-cell resolution. Cell deconvolution by integrating single nucleus RNA-seq of MASH biopsy samples was implemented to determine cell of origin. Bulk RNA-seq analysis of 206 MASLD biopsy samples, stratified by HPC gene signatures, was used to examine differences in clinical parameters and genotype. Finally, clinico-pathological prognostic features of HPCs were assessed in baseline biopsies of MASLD patients with a follow-up biopsy at least one year apart.

Results

A high-throughput transcriptomics analysis of the HPC niche identified 3,282 differentially expressed genes enriched in pro-inflammatory cytokines (e.g. CXCL6, CCL19, CCL2, CCL5, CCL21, SPP1), inflammatory cell markers (e.g. CCR2, CD48, CD8a, CD96, CXCR3, S100A4), as well as antigen presenting genes. Spatial transcriptomics combined with integrated single nucleus RNA-seq uncovered distinct subsets of ductular reaction based on the expression of inflammatory markers SPP1+ and CCL2+. Notably, SPP1+CCL2- ductular reaction localised predominantly within the parenchyma and peri-portal region, while CCL2+SPP1- ductular reaction was confined mainly to the portal tract. Neighbourhood analysis highlighted antigen-presenting cells and IGHA1+IGHG1+ plasma cells in close proximity to ductular reaction. Spatial proteomics validation identified CD48 and HLA-DR-expressing macrophages as key immune cells of the HPC niche. Furthermore, the resulting HPC gene signature stratified transcriptomics data from 206 NAFLD biopsies into distinct clusters characterised by presence of steatohepatitis, high disease activity, fibrosis and AST levels. In a dual biopsy cohort, HPC presence in the parenchyma at baseline was significantly associated with progression of at least 1 fibrosis stage and was able to predict fibrosis progression in MASLD in a binary logistic regression model.

Conclusion

This study identified a pro-inflammatory role for HPCs in patients with MASLD. Furthermore, we showed the clinical relevance of using HPC signatures associated with disease activity and inflammation, as well as their ability to predict fibrosis progression in MASLD patients.

Event

UEG Week Berlin 2025

Topics

Hepatobiliary IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Predicting and understanding early stages of advanced liver disease

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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UEG Presentation

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EXACERBATED COLITIS AND ALTERED METABOLOME IN MICE COLONIZED WITH PRE-DIAGNOSIS MICROBIOME OF HUMANS WITH CROHN’S DISEASE

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EXACERBATED COLITIS AND ALTERED METABOLOME IN MICE COLONIZED WITH PRE-DIAGNOSIS MICROBIOME OF HUMANS WITH CROHN’S DISEASE

Cong Phi Dang 1, Alice Chen-Liaw 2, Mingyue Xue 3, Alexander Luchak 1, Kaiwen Mu 1, Qilong Li 3, Ren Mu Yan 1, Sun-Ho Lee 3, Paul Moayyedi 4, Anne Griffiths 5, Colette Deslandres 6, Sanjay Murthy 7, Allan Hillary Steinhart 8, Anthony Otley 9, Levinus Dieleman 10, Kevan Jacobson 11, David T. Rubin 12, Remo Panaccione 13, Brian G. Feagan 14, Catherine Streutker 15, Ilaria Mogno 2, Graham J. Britton 2, Jeremiah J. Faith 2, Kenneth Croitoiru 3, Williams Turpin 3

Affiliations

1 University of Toronto, Toronto, Canada

2 Icahn School of Medicine at Mount Sinai, New York, United States

3 Mount Sinai Hospital, Toronto, Canada

4 McMaster University Dept. of Medicine Dept. of Gastroenterology - McMaster University Dept. of Medic, Hamilton, Canada

5 Hospital for Sick Children, Toronto, Canada

6 University of Montreal, Montreal, Canada

7 Ottawa Hospital Research Institute, Ottawa, Canada

8 Mount Sinai Hospital Dept. of Medicine, Toronto, Canada

9 Dalhousie University, Halifax, Canada

10 University of Alberta Division of Gastroenterology Dept. of Medicine, Edmonton, Canada

11 British Columbia Children's Hospital, Vancouver, Canada

12 University of Chicago Medicine, Chicago, United States

13 University of Calgary, Calgary, Canada

14 Alimentiv Inc., London, Canada

15 St Michael’s Hospital, Toronto, Canada