A single cell and spatial genomics atlas of human skin fibroblasts in health and disease

Fibroblasts are important for tissue repair and maintenance of immune cell niches across tissues. It remains unclear how the stromal composition of a human organ changes from health across diverse disease contexts. In this study, we integrated ~2 million human single-cell transcriptomes to construct an atlas of 357,276 skin fibroblasts, spanning health and 23 skin disorders. We define 6 major fibroblast populations in health based on gene expression and distinct anatomical niches, establishing a comprehensive spatially-informed atlas of healthy skin. We characterised a fibroblastic reticular cell (FRC)-like subtype in the perivascular niche in health and disease, which appears absent in mouse skin. We predict a likely origin of FRC-like fibroblasts from lymphoid tissue organiser (LTo)-like cells, which we uniquely identified in human prenatal skin. We identified three disease-specific fibroblast subtypes. Inflammatory myofibroblasts (IL11+MMP1+CXCL5+IL7R+) were conserved in inflammatory disorders and cancer across multiple human tissues.