A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues

Abstract Fibroblasts sculpt the architecture and cellular microenvironments of various tissues. Here we constructed a spatially resolved atlas of human skin fibroblasts from healthy skin and 23 skin diseases, with comparison to 14 cross-tissue diseases. We define six major skin fibroblast subtypes in health and three that are disease-specific. We characterize two fibroblast subtypes further as they are conserved across tissues and are immune-related. The first, F3: fibroblastic reticular cell-like fibroblast ( CCL19 + CD74 + HLA-DRA + ), is a fibroblastic reticular cell-like subtype that is predicted to maintain the superficial perivascular immune niche. The second, F6: inflammatory myofibroblasts ( IL11 + MMP1 + CXCL8 + IL7R + ), characterizes early human skin wounds, inflammatory diseases with scarring risk and cancer. F6: inflammatory myofibroblasts were predicted to recruit neutrophils, monocytes and B cells across multiple human tissues. Our study provides a harmonized nomenclature for skin fibroblasts in health and disease, contextualized with cross-tissue findings and clinical skin disease profiles.