Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis
Nature Genetics, vol. 58, pp. 1295–1307
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition impacting over 30% population, yet the dynamic changes in macrophage composition from steatosis to steatohepatitis (metabolic dysfunction-associated steatohepatitis, MASH) remain unclear. Here, by integrating single-nucleus transcriptomics, spatial multi-omics and proteomics on human samples, we delineate the evolving landscape of hepatic macrophages across the MASLD spectrum. Our analysis reveals a progressive depletion of Kupffer cells accompanied by the emergence of diverse, phenotypically distinct macrophage subsets. Spatial multi-omics further demonstrates that disease progression toward MASH is marked by an accumulation of antigen-presenting, phagocytic GPNMB+ macrophages, supported by IL32-producing hepatocytes. These macrophages showed an adaptive metabolic and pro-inflammatory phenotype that is tightly regulated by both spatial context and disease stage. Identified macrophage markers enable patient stratification by disease activity and its stage across independent clinical cohorts. Our study sheds light on the diversity of macrophage identities and metabolic-adaptive phenotypes during the progression of MASLD. This study uses multi-omics approaches to dissect the roles of macrophage populations in the progression of metabolic dysfunction-associated steatohepatitis. GPNMB+ macrophages accumulate in the portal tract in advanced disease and may have antigen-presenting capabilities.
Authors 48
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
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Affiliation as printed
Bruker Spatial Biology, Seattle, WA, USA
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Affiliation as printed
Bruker Spatial Biology, Seattle, WA, USA
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Wallenberg Centre for Molecular and Translational Medicine · University of Gothenburg
Affiliation as printed
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Wallenberg Centre for Molecular and Translational Medicine · University of Gothenburg
Affiliation as printed
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
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Affiliation as printed
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
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Affiliation as printed
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
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Affiliation as printed
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
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Affiliation as printed
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium
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Universitätsklinikum Aachen · University Hospital Carl Gustav Carus · Center for Regenerative Therapies Dresden · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden · RWTH Aachen University
Affiliation as printed
Center for Regenerative Therapies Dresden (CRTD), TUD Dresden University of Technology, Dresden, Germany
Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, TUD Dresden University of Technology, Dresden, Germany
Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany
Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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King's College London · Foundation for Liver Research · King's College Hospital · University of Bari Aldo Moro
Affiliation as printed
Clinica Medica 'C. Frugoni' and Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
Roger Williams Institute of Liver Studies, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Foundation for Liver Research and King's College Hospital, London, UK
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Cambridge University Hospitals NHS Foundation Trust · NIHR Cambridge Biomedical Research Centre
Affiliation as printed
Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge NIHR Biomedical Research Centre, Cambridge, UK
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Affiliation as printed
Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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Centre Hospitalier Universitaire d'Angers
Affiliation as printed
Hepatology Department, Angers University Hospital, Angers, France
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Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · University of Turin
Affiliation as printed
Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
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Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital · Fondation pour l’innovation en Cadiométabolisme et Nutrition
Affiliation as printed
Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Sorbonne University, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
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VIB-KU Leuven Center for Cancer Biology · KU Leuven
Affiliation as printed
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
VIB Center for Cancer Biology, Leuven, Belgium
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Universitätsklinikum des Saarlandes · Saarland University
Affiliation as printed
Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
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VIB-KU Leuven Center for Cancer Biology · KU Leuven
Affiliation as printed
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
VIB Center for Cancer Biology, Leuven, Belgium
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Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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University of Antwerp · Antwerp University Hospital
Affiliation as printed
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
Translational Research in Inflammation and Immunology (TWI2N), Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
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University of Freiburg · University Medical Center Freiburg · Wallenberg Centre for Molecular and Translational Medicine · University of Gothenburg
Affiliation as printed
Institute of Medical Microbiology, Medical centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
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National and Kapodistrian University of Athens · Aretaeio Hospital · Newcastle University
Affiliation as printed
Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Quentin Mark Anstee corresponding
Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle upon Tyne Hospital · NIHR Newcastle Biomedical Research Centre · Newcastle University
Affiliation as printed
Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK. quentin.anstee@newcastle.ac.uk
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. quentin.anstee@newcastle.ac.uk
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Schalk van der Merwe corresponding
Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium. schalk.vandermerwe@uzleuven.be
Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium. schalk.vandermerwe@uzleuven.be
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Olivier Govaere corresponding
Universitair Ziekenhuis Leuven · Newcastle University · KU Leuven
Affiliation as printed
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium. olivier.govaere@kuleuven.be
KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium. olivier.govaere@kuleuven.be
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. olivier.govaere@kuleuven.be
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