Spatial Proteogenomics Reveals Distinct and Evolutionarily Conserved Hepatic Macrophage Niches
Summary
This scholarly work concerns a spatial proteogenomic atlas that pertains to the healthy and obese human and murine liver, integrating advanced techniques including single-cell and -nucleus sequencing alongside spatial mapping of RNA and proteins. The authors offer validated methodologies to discern and position all hepatic cells, with a specific emphasis on hepatic myeloid cells. They provide crucial insights into the biology of these cells, including the identification of reliable surface markers for the isolation and localization of hepatic macrophages, the characterization of lipid-associated macrophages in both healthy and steatotic livers, the determination of a key regulatory axis of Kupffer cell development, and the identification of a conserved core gene expression signature of Kupffer cells across seven distinct species. By implementing this comprehensive approach, the authors provide a multi-dimensional perspective that illuminates previously uncharted aspects of hepatic cell biology.
Fig.1 Graphical abstract. (Guilliams, 2022)
Research Criteria
This scholarly article employs state-of-the-art proteogenomic methods, including CITE-seq and spatial approaches, to pinpoint and characterize all hepatic cells and their exact locations within the healthy and obese livers of both human and mouse subjects. The authors reveal validated strategies to distinguish and locate these cells, including the LAM population at the bile ducts. They also align this atlas across seven different species, unveiling the conserved program of Kupffer cells and LAMs, their cellular niches, and the microenvironmental circuits influencing their distinct transcriptomic identities.
Fig.2 Experimental design. (Guilliams, 2022)
Sample Type
Cells and tissue sections from human and mouse liver.
Result—A Practical Proteogenomics Atlas of the Murine Liver
The authors of this research employed various methods for cell and nucleus isolation from the murine liver, including single-cell and -nucleus RNA sequencing and CITE-seq, to construct an extensive proteogenomic atlas of all hepatic cells. The authors characterized 17 discrete cell types and validated surface markers for each cell type using CITE-seq data. Additionally, the authors compared different isolation methods and determined that each had specific advantages and drawbacks contingent on the biological inquiry. Furthermore, the authors investigated the existence of two Kupffer cell subpopulations (KC1 and KC2) and inferred that they were likely doublets with liver sinusoidal endothelial cells (LSECs) based on CITE-seq data, confocal microscopy, and gene expression analysis.
Fig.3 A practical proteogenomcis atlas of the murine liver. (Guilliams, 2022)
Result—Distinct Spatial Orientation of Hepatic Myeloid Cell Subsets
The present findings explicate the utilization of spatial transcriptomics and proteomics to cartographically depict the topographical distribution of distinct myeloid cell populations within the murine hepatic microenvironment. Notably, the authors uncovered the preponderance of Kupffer cells (KCs) encompassing the central veins while monocyte-derived macrophages (MDMs) and dendritic cells (DCs) were enriched in the vicinity of the portal veins. Moreover, they discovered the localization of lipid-associated macrophages (LAMs), a unique population of macrophages that accumulate lipids, within the biliary tract and that these cells evince a distinctive genetic program implicated in lipid metabolism and inflammation. In addition, the authors delineated that LAMs are stimulated by local lipid exposure and that their number and size increase in obese mice. These observations manifest that LAMs assume a key role in regulating the lipid milieu of the hepatic microenvironment, with profound implications for metabolic homeostasis and inflammatory disease progression.
Fig.4 Distinct spatial orientation of hepatic myeloid cell subsets. (Guilliams, 2022)
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Reference
- Guilliams, M.; et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022, 185(2): 379-396.
