Increased expression of the PIEZO2 mechanoreceptor in fibroblasts and endothelial cells within the lymphatic and vascular vessels of keloids

Abstract Keloids are scars that grow abnormally due to excessive extracellular matrix production by fibroblasts and increased angiogenesis. Chronic tension is implicated in their growth, but the exact pathology remains unclear. This study investigated the increased expression of molecules responsible for sensing pressure in keloids compared with lymphedema, which is also a non‐tumorous fibroproliferative disease caused by another etiology. Higher expression levels of COL1A2 , PIEZO2 , and POSTN were observed in the keloid group compared with the lymphedema group. PIEZO2 expression levels showed a strong correlation with both COL1A2 ( r = 0.9252, 95% CI 0.8474–0.9641, p < 0.001) and POSTN ( r = 0.9118, 95% CI 0.8213–0.9575, p < 0.001). Additionally, PIEZO2 expression levels were significantly higher in recurrent keloids than in non‐recurrent keloids (3,032.5 ± 1,090.2 versus 1,241.9 ± 860.7, p = 0.032). Analysis of gene expression at the single‐cell level found upregulation of PIEZO2 in vascular and lymphatic endothelial cells, and a subgroup of fibroblasts. Additionally, COL1A1 , COL1A2 , COL3A1 , and POSTN expression was also increased in the fibroblast subgroup. Furthermore, in fibroblasts with high PIEZO2 expression, extracellular matrix collagen production signaling was augmented. Histological analysis confirmed the presence of PIEZO2‐positive cells in the perivascular stroma active area of keloid tissue, together with inflammatory cells. Therefore, since PIEZO2‐positive cells are highly expressed specifically in keloids and are deeply involved in their recurrence and activity, we propose that the pathogenesis of keloids is constructed by PIEZO2‐positive cells. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.