Spatial proteogenomics reveals distinct and evolutionarily-conserved hepatic macrophage niches

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.

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

“…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.…”

“…scRNA sequencing data analysis scRNA sequencing data were published before and were analyzed at: https://www.livercellatlas.org/index.php (Guilliams et al, 2022).…”

Unraveling the Complexity of Liver Disease One Cell at a Time

“…While single-cell RNA sequencing (scRNA-seq) has been heavily relied on to map the transcriptomic cellular landscape in liver development, health, CLD, and cancer, recent publications have adopted multimodal single-cell approaches to generate more comprehensive atlases. 13 14 15 16 17 Previous reviews have described the recent efforts toward generating a liver cell atlas using single-cell genomics in detail. 18 This review highlights the unique challenges in studying the liver at a single-cell level, discusses new insights revealed by such approaches, and future opportunities for the application of single-cell technologies to pave the way for effective disease interventions.…”

“…1 ; Tables 1 and 2 for an explanation of these terms), and spatial proteomics to build atlases of the human and murine liver and determine spatial distributions and distinguishable markers for all hepatic cell types. 16 These data were then leveraged for a cross-species analysis to determine an evolutionarily conserved KC and bile-duct macrophage signature and to propose the microenvironmental signals necessary for imprinting their cell identity. Additionally, conventional and plasmacytoid dendritic cells (DC), cells that link the innate and adaptive arms of the immune system, were profiled in healthy and diseased mouse and human livers.…”

“…However, an integrated approach utilizing a multifocal sampling strategy with validation of cell signatures using spatial transcriptomics can enable a more complete and unbiased characterization of the liver in disease. 16 86…”