High-resolution spatial transcriptomics reveals fibroblast and neuroimmune microenvironments in endometriosis lesions, 2026, Haney et al.

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High-resolution spatial transcriptomics reveals fibroblast and neuroimmune microenvironments in endometriosis lesions
Haney, Caroline M; Alizadeh, Elaheh; Lee, Joshua; Sullivan, Meryl; Kuljancic, Jasmina; Flynn, William F; Robson, Paul; White, Brian S; Luciano, Danielle E; Courtois, Elise T

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.

Web | DOI | PDF | Nature Communications | Open Access

 

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An unresolved question in the field is whether neurogenesis results from chronic inflammation or is driven by the presence of lesion-specific epithelial cells and fibroblasts in human tissues. With our data, we show an increase in nociceptor neurons expressing pain receptors close to epithelial glands across both peritoneal and ovarian lesions.

Our in vitro 3D cellular model utilizing sensory brain organoids provides functional evidence of epithelial cells and fibroblasts in promoting sensory pain neurons. Further spatial analysis supports the increased presence of activated macrophages in areas where nociceptor neurons and epithelial glands colocalize. These data suggest a potential synergistic effect whereby epithelial cells influence neurons to express pain receptors. In turn, these neurons likely increase the production of inflammatory molecules (such as NINJ1), promoting the recruitment and activation of immune cells, particularly macrophages, and contributing to the sustained inflammatory microenvironment.