Multitranscriptome analysis reveals stromal cells in the papillary dermis to promote angiogenesis in psoriasis vulgaris

BACKGROUND: The pathogenesis of psoriasis is incompletely understood. Growing evidence suggests the involvement of stromal cells in the inflammatory process. OBJECTIVES: To investigate the roles of stromal cells, including fibroblasts, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), in the psoriatic inflammatory microenvironment, and the possible underlying mechanisms involved. METHODS: We used a combination of single-cell, spatial transcriptome and bulk RNA sequencing of lesional and nonlesional skin samples from patients with psoriasis vulgaris (PV) and healthy skin samples from unaffected individuals. RESULTS: By analysing transcriptomes from 364 098 single cells, we uncovered WNT5A+ (Wnt-5a) fibroblasts, ITIH5+ (inter-α-trypsin inhibitor heavy chain 5) VECs and VCAN+ (versican) VSMCs, with significantly increased proportions of these cells in the papillary dermis of lesional psoriatic skin. We defined eight unique subclusters of fibroblasts in the skin and observed a shift of WIF1+ (Wnt inhibitory factor 1) fibroblasts toward WNT5A+ fibroblasts, with abnormal activation of the noncanonical Wnt signalling pathway and increased angiogenic and proinflammatory capabilities. VSMCs were able to undergo phenotypic transformation from a contractile to a synthetic phenotype during the development of psoriatic inflammation. ITIH5+ VECs and VCAN+ VSMCs were found to have an essential role in regulating angiogenesis and vascular remodelling in the pathological changes seen in PV. Ligand receptor analyses found that WNT5A+ fibroblasts are extensively implicated in interactions with various skin cell types, especially TIH5+ VECs and VCAN+ VSMCs in the papillary dermis. CONCLUSIONS: Interactions of stromal cells in the papillary dermis were identified as possible pathogenic elements in PV. Improving the inflammatory microenvironment by targeting stromal cells might be a potential treatment strategy in PV.