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 47

1. Markus Boesch

   KU Leuven

   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

2. Seray Anak

   KU Leuven

   Affiliation as printed

   Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium

3. Dania El Abyad

   KU Leuven

   Affiliation as printed

   Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium

4. Tessa Ostyn

   KU Leuven

   Affiliation as printed

   Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium

5. Asier Antoranz

   KU Leuven

   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

6. Trieu My Van
   Affiliation as printed

   Bruker Spatial Biology, Seattle, WA, USA

7. Daniel Newhouse
   Affiliation as printed

   Bruker Spatial Biology, Seattle, WA, USA

8. Caitlyn Myers

   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

9. Lukas Van Melkebeke

   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

10. Jeremy M. Palmer

    Newcastle University

    Affiliation as printed

    Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

11. Najmeh Saffarzadeh

    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

12. Jonathan Sai‐Hong Chui

    KU Leuven

    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

13. Rita Feio‐Azevedo

    KU Leuven

    Affiliation as printed

    Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium

14. Lena Smets

    KU Leuven

    Affiliation as printed

    Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium

15. Nikolina Dubroja

    KU Leuven

    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

16. Paula Longás Calvo

    KU Leuven

    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

17. Thierry Voet

    KU Leuven

    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

18. James A. Clark

    Newcastle University

    Affiliation as printed

    Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

19. Simon Cockell

    Newcastle University

    Affiliation as printed

    Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

20. Matthias Lannoo

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium

21. Ellen Deleus

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium

22. Joris Jaekers

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium

23. Halit Topal

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium

24. Baki Topal

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium

25. Kai Markus Schneider Aachen Medical Clinic III

    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

26. Michele Vacca

    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

27. Michael Allison

    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

28. Mattias Ekstedt

    Linköping University

    Affiliation as printed

    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden

29. Jérôme Boursier

    Centre Hospitalier Universitaire d'Angers

    Affiliation as printed

    Hepatology Department, Angers University Hospital, Angers, France

30. Elisabetta Bugianesi

    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

31. Vlad Ratziu

    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

32. Frederik De Smet

    KU Leuven

    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

33. Bram Boeckx

    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

34. Ann K. Daly

    Newcastle University

    Affiliation as printed

    Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

35. Jörn Markus Schattenberg

    Universitätsklinikum des Saarlandes · Saarland University

    Affiliation as printed

    Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany

36. Jef Verbeek

    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

37. Francesca Maria Bosisio

    KU Leuven

    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

38. Diether Lambrechts

    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

39. Tania Roskams

    KU Leuven

    Affiliation as printed

    Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium

40. Carolin V. Schneider Aachen Medical Clinic III

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany

41. Sven Francque

    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

42. Hannelie Korf

    KU Leuven

    Affiliation as printed

    Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium

43. Anetta Härtlová

    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

44. DINA G. TINIAKOS

    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

45. 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

46. S 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

47. 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