Cross-species spatial transcriptomics of hepatic zonation in mouse and human

Abstract

The liver’s portal–central axis organizes hepatocyte biology into periportal, mi dzonal, and pericentral programs that lead energy metabolism, xenobiotic clearance, and endocrine control. How these spatial programs intersect with sex-biased transcription—and whether mouse models mirror human biology—remains unclear. We applied Visium CytAs sist spatial transcriptomics to formalin-fixed paraffin-embedded liver sections from balanced male/female cohorts (mouse n = 10; human n = 19). After stringent quality control and hepatocyte enrichment, we reconstructed zonation by landmark-based scoring and mapped expression across periportal, midzonal, and pericentral regions. Zonation emerged as a sta ble organizing principle in both species. Sex effects, however, were strongly context-depend ent. In mouse, sex-biased expression was pronounced and modulated by lobular position, with many transcripts showing differences that were specific to liver compartments (i.e., sex effects that depend on zone). In human, sex differences were weaker, typically confined to particular compartments, and involved distinct sets of metabolic, structural, and immune genes. Cross-species ortholog comparisons revealed limited concordance: gene-level agreement was low and pathway overlaps were sparse. Part of this gap likely reflects true biological differences; additional attenuation likely stems from platform limits—probe-capture bias, transcript drop-out, and the multi-cellular averaging of Visium spots-rather than formalin fixation per se. Overall, liver zonation is conserved, whereas sex-dependent gene expression is not uniformly shared between mouse and human. The results argue for spatial- and sex aware study designs and careful, assay-level validation before translating mouse findings to human drug development or safety assessment.