Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

• Published in: Cell Vol. 185; no. 2; pp. 379 - 396.e38
• Main Authors: Guilliams, Martin, Bonnardel, Johnny, Haest, Birthe, Vanderborght, Bart, Wagner, Camille, Remmerie, Anneleen, Bujko, Anna, Martens, Liesbet, Thoné, Tinne, Browaeys, Robin, De Ponti, Federico F., Vanneste, Bavo, Zwicker, Christian, Svedberg, Freya R., Vanhalewyn, Tineke, Gonçalves, Amanda, Lippens, Saskia, Devriendt, Bert, Cox, Eric, Ferrero, Giuliano, Wittamer, Valerie, Willaert, Andy, Kaptein, Suzanne J.F., Neyts, Johan, Dallmeier, Kai, Geldhof, Peter, Casaert, Stijn, Deplancke, Bart, ten Dijke, Peter, Hoorens, Anne, Vanlander, Aude, Berrevoet, Frederik, Van Nieuwenhove, Yves, Saeys, Yvan, Saelens, Wouter, Van Vlierberghe, Hans, Devisscher, Lindsey, Scott, Charlotte L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2022; Cell Press
• Subjects: across species; Animals; Biological Evolution; Cell Nucleus - metabolism; CITE-seq; Fatty Liver - genetics; Fatty Liver - pathology; Hepatocytes - metabolism; Homeostasis; Humans; Kupffer cell; Kupffer Cells - metabolism; Leukocyte Common Antigens - metabolism; lipid-associated macrophage; Lipids - chemistry; liver; Liver - metabolism; Lymphocytes - metabolism; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Models, Biological; multi-omic; Myeloid Cells - metabolism; NAFLD; Obesity - pathology; proteogenomic; Proteogenomics; Proteome - metabolism; Resource; Signal Transduction; spatial transcriptomics; Transcriptome - genetics; lipid-associated macrophage; Kupffer cell; NAFLD; multi-omic; liver; atlas; spatial transcriptomics; CITE-seq; proteogenomic; across species
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.12.018

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. [Display omitted] •Spatial proteogenomic single-cell atlas of healthy and obese murine and human liver•Validated flow cytometry and microscopy panels for all hepatic cells•LAMs are differentially located in the lean and obese liver•Evolutionary conserved BMP9/10-ALK1 axis is essential for KC development By combining single-cell and -nucleus sequencing with spatial mapping of RNA and proteins, this vast spatial proteogenomic atlas of healthy and obese human and mouse livers presents methods to identify and localize all hepatic cells and provides insights into hepatic myeloid cells, including identification of reliable surface markers for isolation and localization of hepatic macrophages, characterization of lipid-associated macrophages in both healthy and steatotic livers, determination of a key regulatory axis of Kupffer cell development, and identification of a conserved core gene expression signature of Kupffer cells across 7 species, including chickens and zebrafish.