Spatial proteogenomics reveals distinct and evolutionarily-conserved hepatic macrophage niches
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
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 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. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and bile-duct macrophages. We also uncover the respective spatially-resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that bile-duct macrophages are induced by local lipid exposure, while Kupffer cells crucially depend on their crosstalk with hepatic stellate cells via the evolutionarily-conserved ALK1-BMP9/10 axis.
Authors 36
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Martin Guilliams corresponding
Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, 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 7, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, 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 7, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, 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 7, Ghent 9052, Belgium
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Affiliation as printed
Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Belgium
Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver research Center, Ghent University, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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 Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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
Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 7, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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
Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 7, Ghent 9052, Belgium
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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
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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 Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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 Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, 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 7, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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
Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 7, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, 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
Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 7, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium
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Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium
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Affiliation as printed
Laboratory of Immunology, Department Virology Parasitology Immunology and Comparative Physiology, Faculty of Veterinary Medicine, Ghent University, Belgium
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Affiliation as printed
Laboratory of Immunology, Department Virology Parasitology Immunology and Comparative Physiology, Faculty of Veterinary Medicine, Ghent University, Belgium
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Affiliation as printed
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium
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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
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Affiliation as printed
Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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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
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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
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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
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Affiliation as printed
Laboratory of Parasitology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium
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Affiliation as printed
Laboratory of Parasitology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium
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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, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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Peter ten Dijke Aachen Oncode Institute Department of Molecular Cell Biology and Center for Cancer Genomics Leiden Medical Center
Leiden University Medical Center
Affiliation as printed
Oncode Institute, Department of Molecular Cell Biology and Center for Cancer Genomics, Leiden Medical Center, Leiden, Netherlands
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Affiliation as printed
Department of Pathology, Ghent University Hospital, Ghent 9000, Belgium
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Affiliation as printed
Department of General and Hepatopancreatobiliary Surgery and Liver Transplantation, Ghent University Hospital, Ghent 9000, Belgium
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Affiliation as printed
Department of General and Hepatopancreatobiliary Surgery and Liver Transplantation, Ghent University Hospital, Ghent 9000, Belgium
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Affiliation as printed
Department of Human Structure and Repair, Ghent University Hospital, Ghent 9000, Belgium
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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
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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, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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Affiliation as printed
Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver research Center, Ghent University, Belgium
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Affiliation as printed
Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Belgium
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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, Ghent, 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 Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 902, Belgium
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