Mapping spatially-resolved transcriptomes in systemic sclerosis

Systemic sclerosis (SSc) is a prototypical fibrotic disease with high mortality and limited treatment options. Despite advances in single-cell RNA sequencing (scRNA-seq) providing deep understanding of cellular heterogeneity, their interaction within the fibrogenesis microenvironment remains elusive. We here generated spatially resolved transcriptome maps from healthy and SSc skin to address these limitations. We built a scRNA-seq atlas of human skin and mapped the data to spatial space, enabling us to identify a fibrotic niche, enriched with fibroblasts and macrophages, that is significantly expanded in SSc and correlated with clinical outcome. We identified SSs-specific cell states of fibroblasts, macrophages, and endothelial cells, and evaluated their spatial dependency on each other. We identified CXCL12/ACKR3/CXCR4 as a regulatory axis in shifting from homeostatic to fibrotic state in SSc, highlighting its role in endothelial-macrophage-fibroblast interplay. Together, we provided an in-depth description at cellular and spatial level of colocalization events occurring in SSc, offering spatiotemporal insights.