Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

Cell, vol. 185, pp. 379–396.e38

Abstract

The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.

Authors 37

1. Martin Guilliams corresponding

   Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium. Electronic address: martin.guilliams@ugent.be

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

2. Johnny Bonnardel

   Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

3. Birthe Haest

   Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

4. Bart Vanderborght

   Ghent University

   Affiliation as printed

   Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium; Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center, Ghent University, Belgium

   Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center, Ghent University, Belgium

   Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium

5. Camille Wagner

   Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

6. Anneleen Remmerie

   Vlaams Instituut voor Biotechnologie · Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

7. Anna Bujko

   Vlaams Instituut voor Biotechnologie · Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

8. Liesbet Martens

   Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

9. Tinne Thoné

   Ghent University · VIB-UGent Center for Inflammation Research

   Affiliation as printed

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

   Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

   Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

10. Robin Browaeys

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Data Mining and Modelling for Biomedicine, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Faculty of Science, Ghent University, Ghent, Belgium

    Data Mining and Modelling for Biomedicine, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Applied Mathematics, Computer Science and Statistics, Faculty of Science, Ghent University, Ghent, Belgium

11. Federico F. De Ponti

    Vlaams Instituut voor Biotechnologie · Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

12. Bavo Vanneste

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

13. Freya R. Svedberg

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

14. Tineke Vanhalewyn

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

15. Amanda Costa Gonçalves

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

16. Saskia Lippens

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

17. Bert Devriendt

    Ghent University

    Affiliation as printed

    Laboratory of Immunology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Belgium

18. Eric Cox

    Ghent University

    Affiliation as printed

    Laboratory of Immunology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Belgium

19. Giuliano Ferrero

    Université Libre de Bruxelles

    Affiliation as printed

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium

20. Valérie Wittamer

    Université Libre de Bruxelles · Walloon Excellence in Lifesciences and Biotechnology

    Affiliation as printed

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium; ULB Institute of Neuroscience (UNI), Université Libre de Bruxelles (ULB), Brussels, Belgium; WELBIO, Université Libre de Bruxelles (ULB), Brussels, Belgium

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium

    ULB Institute of Neuroscience (UNI), Université Libre de Bruxelles (ULB), Brussels, Belgium

    WELBIO, Université Libre de Bruxelles (ULB), Brussels, Belgium

21. Andy Willaert

    Ghent University

    Affiliation as printed

    Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

22. Suzanne J. F. Kaptein

    Rega Institute for Medical Research · KU Leuven

    Affiliation as printed

    KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Molecular Vaccinology and Vaccine Discovery, Leuven, Belgium

23. Johan H. Neyts

    Rega Institute for Medical Research · KU Leuven

    Affiliation as printed

    KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Molecular Vaccinology and Vaccine Discovery, Leuven, Belgium

24. Kai Dallmeier

    Rega Institute for Medical Research · KU Leuven

    Affiliation as printed

    KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Molecular Vaccinology and Vaccine Discovery, Leuven, Belgium

25. Peter Geldhof

    Ghent University

    Affiliation as printed

    Laboratory of Parasitology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium

26. Stijn Casaert

    Ghent University

    Affiliation as printed

    Laboratory of Parasitology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium

27. Bart Deplancke

    SIB Swiss Institute of Bioinformatics · École Polytechnique Fédérale de Lausanne

    Affiliation as printed

    Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

    Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

28. Peter ten Dijke Aachen Oncode Institute Department of Cell and Chemical Biology Leiden Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Oncode Institute, Department of Cell and Chemical Biology, Leiden Medical Center, Leiden, Netherlands

29. Anne Hoorens

    Ghent University Hospital

    Affiliation as printed

    Department of Pathology, Ghent University Hospital, Ghent 9000, Belgium

30. Aude Vanlander

    Ghent University Hospital

    Affiliation as printed

    Department of General and Hepatopancreatobiliary Surgery and Liver Transplantation, Ghent University Hospital, Ghent 9000, Belgium

31. Frederik Christiaan Berrevoet

    Ghent University Hospital

    Affiliation as printed

    Department of General and Hepatopancreatobiliary Surgery and Liver Transplantation, Ghent University Hospital, Ghent 9000, Belgium

32. Yves Van Nieuwenhove

    Ghent University Hospital

    Affiliation as printed

    Department of Human Structure and Repair, Ghent University Hospital, Ghent 9000, Belgium

33. Yvan Saeys

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Data Mining and Modelling for Biomedicine, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Faculty of Science, Ghent University, Ghent, Belgium

    Data Mining and Modelling for Biomedicine, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium

    Department of Applied Mathematics, Computer Science and Statistics, Faculty of Science, Ghent University, Ghent, Belgium

34. Wouter Saelens

    SIB Swiss Institute of Bioinformatics · École Polytechnique Fédérale de Lausanne

    Affiliation as printed

    Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

    Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

35. Hans Van Vlierberghe

    Ghent University Hospital · Ghent University

    Affiliation as printed

    Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium

    Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium

    Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium

36. Lindsey Devisscher

    Ghent University

    Affiliation as printed

    Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center, Ghent University, Belgium

37. Charlotte L. Scott corresponding

    Ghent University · VIB-UGent Center for Inflammation Research

    Affiliation as printed

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium. Electronic address: charlotte.scott@ugent.be

    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium