Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

Guilliams, Martin; Bonnardel, Johnny; Haest, Birthe; Vanderborght, Bart; Wagner, Camille; Remmerie, Anneleen; Bujko, Anna; Martens, Liesbet; Thoné, Tinne; Browaeys, Robin; Ponti, Federico; Vanneste, Bavo; Zwicker, C.; Svedberg, Freya R; Vanhalewyn, Tineke; Gonçalves, Amanda; Lippens, Saskia; Devriendt, Bert; Cox, Eric; Ferrero, Giuliano; Wittamer, Valérie; Willaert, Andy; Kaptein, Suzanne; Neyts, Johan; Dallmeier, Kai; Geldhof, Peter; Casaert, Stijn; Deplancke, Bart; Dijke, Peter ten; Hoorens, Anne; Vanlander, Aude; Berrevoet, Frederik; Nieuwenhove, Yves Van; Saeys, Yvan; Saelens, Wouter; Vlierberghe, Hans Van; Devisscher, Lindsey; Scott, Charlotte

doi:10.1016/j.cell.2021.12.018

Cited by 406 publications

(466 citation statements)

References 62 publications

Supporting

Mentioning

421

Contrasting

Unclassified

Order By: Relevance

“…An unbiased single-cell RNA sequencing (scRNA-seq) approach identified a subpopulation of circulating monocyte-derived scar-associated TREM2 + CD9 + macrophages (SAMs) that spatially accumulate within the fibrotic niche of cirrhotic human livers (12). Trem2-and Cd9expressing hepatic lipid-associated macrophages (LAMs) have also been described recently in metabolic-associated fatty liver disease (13)(14)(15). However, the role of TREM2 in human cancer is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis Highlights the Immunosuppressive Role of TREM2+ Macrophages in Hepatocellular Carcinoma

et al. 2022

View full text Add to dashboard Cite

Recently, attention has been focused on the central role of TREM2 in diverse pathologies. However, the role of TREM2 signaling in the tumor microenvironment of hepatocellular carcinoma (HCC) remains poorly understood. Herein, we systematically investigated the single-cell transcriptomes of human HCC tissues and found that TREM2 was predominantly expressed by a macrophage subpopulation enriched in tumor tissues that resemble lipid-associated macrophages (LAMs). The accumulation of TREM2+ LAM-like cells in HCC was confirmed in two additional cohorts using scRNA-seq analysis and immunohistochemistry. High expression of TREM2 correlated with high infiltrating macrophage abundance and poor prognosis. Based on systematic interrogations of transcriptional profiles and cellular interactions, TREM2+ LAM-like cells were identified to mainly originate from S100A8+ monocytes and represented an immunosuppressive state. TREM2+ LAM-like cells recruited suppressive Treg cells, facilitating microenvironment remodeling. Furthermore, gene regulatory analysis and in vitro functional assays indicated that activation of LXR signaling could promote the reprogramming of TREM2+ LAM-like cells. Correlation analysis of bulk RNA-sequencing data demonstrated that the enrichment of TREM2+ LAM-like cells was an independent indicator of adverse clinical outcomes in HCC patients. Our comprehensive analyses provide deeper insights into the immunosuppressive role of TREM2+ LAM-like cells in HCC.

show abstract

Section: Introductionmentioning

confidence: 99%

Integrated Analysis Highlights the Immunosuppressive Role of TREM2+ Macrophages in Hepatocellular Carcinoma

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The Wnt/β-catenin signaling pathway is an evolutionarily conserved pathway with vital cellular functions. Since the Wnt/β-catenin signaling pathway is important for liver function, we sought to query the expression of various Wnt genes in various liver cells through examination of public scRNA sequencing data from different species (Guilliams et al, 2022). In the human dataset, 18 out of 19 WNTs were detected in various hepatic cell types (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Liu

Bian

et al. 2022

Preprint

View full text Add to dashboard Cite

The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of b-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Conditional EC-elimination of Wnt2 and Wnt9b led to perturbation of LZ with not only loss of b-catenin targets in zone 3, but also re-appearance of zone 1 genes in zone 3, unraveling dynamicity as revealed by single-cell spatial transcriptomics using Molecular Cartography. Defective LR observed in the knockouts phenocopied other models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts. Molecular Cartography on the livers of the agonist-treated animal revealed changes in LZ. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.

show abstract

“…Furthermore, since nuclei, unlike cells, also are resistant to freeze-thaw manipulation, snRNAseq can also be performed on frozen archived material. While multiple studies using snRNAseq have been reported on the heart [91], only two studies using snRNAseq on the liver have been reported to our knowledge [92,93].…”

Section: Technological Progress In Assessing Endothelial Cell Heterog...mentioning

confidence: 98%

“…A second revolution in the 'omics area' is the departure from a 'transcriptomics-centric' view through combining/cumulating different 'omics' analyses, such that information is obtained not only on the transcriptome, but also on the proteome and the epigenome (Figure 3B) [92,93,[96][97][98][99][100][101][102][103]. At this time, however, single-cell analyses at the level of proteins and their post-translationally modified versions remain a technical challenge.…”

Section: Technological Progress In Assessing Endothelial Cell Heterog...mentioning

confidence: 99%

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity

Gifre-Renom

Daems

Luttun

et al. 2022

IJMS

View full text Add to dashboard Cite

Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture.

show abstract

Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

Cited by 406 publications

References 62 publications

Integrated Analysis Highlights the Immunosuppressive Role of TREM2+ Macrophages in Hepatocellular Carcinoma

Integrated Analysis Highlights the Immunosuppressive Role of TREM2+ Macrophages in Hepatocellular Carcinoma

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity

Contact Info

Product

Resources

About