LPS stimulation reveals male and female dimorphism in human iPSC-derived macrophages

Clinical disparities in the inflammatory responses between males and females have been reported for decades, revealing sex-biased disease severity and patient outcomes. To better understand the intrinsic biological sex differences contributing to these disparities, we characterized the functional and transcriptomic responses of induced pluripotent stem cell (iPSC)-derived macrophages from male and female donors under control and inflammatory conditions using the bacterial antigen lipopolysaccharide (LPS). Bulk RNA sequencing identified 67 genes differentially expressed between male and female macrophages in the absence of inflammation, the majority of which mapped to the sex chromosomes. This sexual dimorphism was amplified by LPS stimulation, with genes predominantly located on autosomes, leading to divergent patterns in secreted protein production that were consistent with clinical findings following LPS exposure. Although future validation with a larger patient cohort is needed, these data collectively suggest that iPSC-derived macrophages can serve as a meaningful tool for understanding and improving treatment of sex-biased pathophysiological conditions.