Integrated Single-Cell and Spatial Transcriptomic Analysis Reveals a Pathological Niche Formed by FAP+ Fibroblasts, Immune, and Endothelial Cells in Psoriatic Lesions.

Purpose: The dysregulated immune microenvironment represents a key pathogenic driver in psoriatic lesions. However, the intricate cellular and molecular interactions underlying psoriasis remain incompletely elucidated. Therefore, we aim to employ integrated multi-omics approaches to characterize the immune microenvironment and pathogenic niche in psoriasis, thereby elucidating the cellular and molecular mechanisms of disease pathogenesis. Methods: Integrated Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA sequencing (RNA-seq) data to explore the heterogeneity of stromal cells and immune cells in psoriatic lesions and the complex spatial niches formed between them. Enrichment analysis, intercellular communication analysis, and spatial co-localization analysis were used to investigate the transcriptional changes and distribution characteristics of each cell type in the lesions of psoriasis patients. Results: Using scRNA-seq, we identified a novel CD4+ tissue-resident memory T cell (TRM) subset that is exclusively present in lesional skin of psoriasis patients but absent in healthy skin. These cells exhibit elevated expression of genes including IL17RA, IL22, PD1 (PDCD1), CXCR6, ITGAE, CD69, TNFRSF9, TNFRSF4, IL7R, CD4, and STAT3. Additionally, we discovered a novel microvascular endothelial cell subset, designated Venous endo2, which highly expresses CD93, ACKR1, ICAM1, VCAM1, IL15, SELE, and SELP, while also overlapping with high endothelial venule (HEV)-associated transcriptional signatures. Integrated analysis of scRNA-seq and spatial transcriptomics further revealed strong spatial co-localization of Venous endo2 with fibroblast activation protein-positive fibroblasts (FAP+ Fbs), T cells, and antigen-presenting cells (APCs) in Psoriasis lesions-a pattern not observed in healthy control skin. Conclusion: Through integrated multi-omics analysis, we identified a potential pathogenic niche in psoriasis patients, composed of Venous endo2, FAP+ Fbs, T cells, and APCs. This structure resembles tertiary lymphoid structures (TLS), suggesting a functional parallel in disease pathogenesis.