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

Abstract 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.