Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

TLDR

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. The atlas combines single‑cell CITE‑seq, single‑nuclei sequencing, spatial transcriptomics, and spatial proteomics. The atlas enables reliable discrimination and localization of all hepatic cells, identifies lipid‑associated macrophages at bile ducts, aligns conserved Kupffer cell and LAM programs across seven species, maps their spatial niches and microenvironmental circuits, shows LAMs are induced by local lipid exposure in steatotic regions, and links Kupffer cell development to stellate‑cell cross‑talk via the evolutionarily conserved ALK1‑BMP9/10 axis.

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 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.