High-resolution spatial transcriptomics reveals fibroblast and neuroimmune microenvironments in endometriosis lesions

Endometriosis is a chronic, systemic, inflammatory disease characterized by the presence of endometrium-like tissue growing outside of the uterus. Affecting one in ten individuals assigned female at birth, it causes chronic pain and inflammation that significantly impairs quality of life. Yet the mechanisms that drive pain and disease progression remain poorly defined. This study establishes the precise spatial transcriptomic cartography of human ovarian and peritoneal lesions, two of the most commonly found lesions. We identify shared spatial features across lesion types, including immune cell infiltration, fibroblast compartments surrounding epithelial glands, and distinct distributions of neuronal and macrophage subsets. We precisely defined sensory neuronal subtypes and mapped their spatial location relative to immune cells. We further validate the epithelial-neuronal interactome, using an in vitro 3D model of peripheral sensory brain organoids co-cultured with human endometriosis epithelial and fibroblast cells. By mapping spatial cellular interactions and conserved features across lesion types linked to pain, our study advances understanding of endometriosis pathophysiology and informs targeted therapeutic development. Haney et al. map human endometriosis lesions and reveal shared cellular organization across endometriosis lesion types, identifying fibroblast compartments, neuro-immune interactions, and painsensing neurons, modeled in 3D co-culture systems.