Spatially resolved gene programs and cell neighborhoods of scleroderma fibroblasts 2261024

Abstract Introduction Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune disease with high mortality, characterized by progressive fibrosis of the skin and internal organs. Skin involvement is among the earliest manifestations of disease, and changes in skin pathology can mirror systemic progression. While single-cell studies have revealed striking transcriptional diversity among dermal fibroblasts in SSc, the spatial organization and immune signals that govern their function remain unclear. Methods To address this, we performed high-resolution spatial transcriptomic profiling of clinically affected and unaffected skin from SSc donors alongside healthy controls. Results We identify known disease-associated fibroblast subsets, including COMP+ myofibroblasts, which localize within cell neighborhoods enriched in activated endothelial and immune cells. In contrast, LGR5+/PI16+ fibroblasts — abundant in healthy skin and previously shown to contain a T cell-inducible gene program — are significantly reduced in both clinically involved and uninvolved SSc skin and occupy distinct microenvironments from disease-associated cells. Conclusion Our findings provide a spatial framework for understanding fibroblast heterogeneity and identify potential therapeutic strategies aimed at reinforcing protective fibroblast programs to prevent or delay fibrosis in scleroderma. Funding Source R21AI185642 NIAID/NIH, National Scleroderma Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)