Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

Area of Science:

• Hepatology
• Immunology
• Systems Biology

Background:

• The liver, the body's largest solid organ, requires further characterization.
• Understanding liver cell heterogeneity and spatial organization is crucial for disease research.

Purpose of the Study:

• To create a spatial proteogenomic atlas of healthy and obese human and murine livers.
• To identify and localize all hepatic cell types, including lipid-associated macrophages (LAMs).
• To investigate the conserved cellular niches and microenvironmental drivers of macrophage identity across species.

Main Methods:

• Integration of multi-omic datasets: single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics.
• Development of validated strategies for hepatic cell discrimination and localization.
• Cross-species alignment of liver atlases.

Main Results:

• A comprehensive spatial proteogenomic atlas of the liver was generated.
• Lipid-associated macrophages (LAMs) were identified and localized near bile ducts.
• Conserved Kupffer cell and LAM programs were revealed across seven species.
• Spatially resolved cellular niches and microenvironmental circuits influencing macrophage identity were uncovered.
• LAM induction by local lipid exposure in steatotic regions was demonstrated.
• Kupffer cell development was shown to depend on hepatic stellate cell cross-talk via the ALK1-BMP9/10 axis.

Conclusions:

• The study provides a high-resolution spatial atlas for liver cell characterization.
• LAMs are a distinct macrophage population induced by lipid exposure in the liver.
• Kupffer cell development is regulated by specific hepatic microenvironmental interactions.