Liao Caihe, Wang Peiru, Zeng Qingyu, Yan Guorong, Gao Jiawen, Liu Jia, Yan Jia, Zhang Guolong, Liu Yeqiang, Wang Xiuli
Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Pathology at Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
J Invest Dermatol. 2025 Apr 18. doi: 10.1016/j.jid.2025.03.039.
Keloids are fibroproliferative diseases affecting millions of people worldwide, but curing keloids remains challenging. Mechanical force is a common initiator and driver of keloids, and blocking the proadhesive signaling pathways is expected to cure keloids. This study found higher levels of Piezo1 in human keloid fibroblasts than in normal skin fibroblasts. Single-cell transcriptome analysis revealed a correlation of Piezo1 with Yes-associated protein (YAP) in keloid fibroblasts. Knockdown of Piezo1/YAP in keloid fibroblasts versus fibroblasts decreased CCN2 and CCN1 expression and fibrosis-related cell behaviors, identifying Piezo1 and YAP as upstream signals of proadhesive signaling loop in keloids. Treatment of patient-derived keloid xenograft model with Piezo1 inhibitor GsMTx4 and YAP inhibitor verteporfin reduced keloid volume and decreased type I/III collagen ratio. Atomic force microscopy further confirmed the biomechanical improvements of keloids in elasticity, viscoelasticity, and roughness ex vivo. In addition, the calcium ion-sensitive fluorescent indicator Fluo-3/AM and double-labeling immunofluorescence stains showed that Piezo1 transferred mechanosignal to increase YAP nuclear translocation through calcium flux. Finally, transcriptomics revealed target genes of the Piezo1/YAP signaling pathway, such as TBX3, SESN2, SMAD7, FOSB, JARID2, and HAS2. Consequently, the Piezo1/calcium flux/YAP signaling axis contributes to the mechanically induced proadhesive signaling pathway, and thus, Piezo1 and YAP are promising targets for keloid treatment.
瘢痕疙瘩是一种影响全球数百万人的纤维增生性疾病，但治愈瘢痕疙瘩仍然具有挑战性。机械力是瘢痕疙瘩常见的引发因素和驱动因素，阻断促黏附信号通路有望治愈瘢痕疙瘩。本研究发现，人类瘢痕疙瘩成纤维细胞中Piezo1的水平高于正常皮肤成纤维细胞。单细胞转录组分析揭示了瘢痕疙瘩成纤维细胞中Piezo1与Yes相关蛋白（YAP）之间的相关性。与成纤维细胞相比，敲低瘢痕疙瘩成纤维细胞中的Piezo1/YAP可降低CCN2和CCN1的表达以及纤维化相关的细胞行为，确定Piezo1和YAP是瘢痕疙瘩中促黏附信号环的上游信号。用Piezo1抑制剂GsMTx4和YAP抑制剂维替泊芬治疗患者来源的瘢痕疙瘩异种移植模型可减小瘢痕疙瘩体积并降低I/III型胶原蛋白比例。原子力显微镜进一步证实了瘢痕疙瘩在体外弹性、黏弹性和粗糙度方面的生物力学改善。此外，钙离子敏感荧光指示剂Fluo-3/AM和双标记免疫荧光染色显示，Piezo1通过钙流传递机械信号以增加YAP核转位。最后，转录组学揭示了Piezo1/YAP信号通路的靶基因，如TBX3、SESN2、SMAD7、FOSB、JARID2和HAS2。因此，Piezo1/钙流/YAP信号轴促成了机械诱导的促黏附信号通路，因此，Piezo1和YAP是瘢痕疙瘩治疗有前景的靶点。
