PIEZO2 mechanoreceptor-expressing fibroblasts in keloids cause short-term recurrence after surgical resection

Keloids are characterized by persistent scar tissue growth that causes abnormal sensory perceptions due to mechanical stress. But the molecular dysfunction and disease-specific cells that fashion keloid pathophysiology are still not evident. Here, we found a distinct subpopulation of fibroblasts with enhanced expression of PIEZO2 in the dermal layer of keloid patients experiencing dysesthesia, including pain and pressure-tactile itch. The PIEZO2-expressing fibroblasts exhibited a keloid-typical phenotype marked by increased extracellular matrix production signaling and higher levels of collagens such as COL1A1, COL1A2, and COL3A1 compared with other fibroblasts. Notably, patients with higher PIEZO2 expression tend to experience keloid recurrence more quickly after keloidectomy (4/5 vs. 0/5, p = 0.047) than those with lower PIEZO2 expression. Thus, the PIEZO2-positive fibroblasts are indicative cells that most accurately reflect the keloid characteristics, suggesting the driving role for the persistent growth of Keloids. According to the supplier's manual, total RNA purification was performed using an RNeasy Plus Kit (QIAGEN) with an RNase-free DNase Set (QIAGEN) described in our previous study 9. In brief, twenty 4um-thick thin sections were cut from cryopreserved skin tissue using a cryostat, dissolved in Lysis Buffers in the RNAeasy Kit to extract total RNA. The quality and amount of the RNA in each sample were evaluated using Experion (Bio-Rad, Hercules, CA, USA) and NanoDrop (Thermo Fisher Scientific), respectively. RNA-seq analysis was performed by Operon biotechnology.