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), the comprehensive understanding of cellular heterogeneity and cell-cell interaction within the fibrogenesis microenvironment remains limited. We generated spatially resolved transcriptome maps from healthy and SSc skin and built a scRNA-seq atlas to map the single-cell data to spatial space. This enabled us to identify a fibrotic niche, enriched with fibroblasts and macrophages, which is significantly expanded in SSc and correlated with clinical outcome. We revealed disease-specific cell states of fibroblasts and macrophages, and evaluated their spatial dependency on other cell types. We identified selective expression of ACKR3 in fibroblast progenitors that diminishes with SSc progression, which may serve to regulate CXCL12/CXCR4-mediated macrophage recruitment and fibrotic remodeling. Together, we provided an in-depth description at cellular and spatial level of fine-tuned regulatory events occurring in SSc, offering spatiotemporal insights.