皮肤伤口愈合是一个复杂而有组织的生物过程,真皮成纤维细胞起着至关重要的作用。已知α-连环蛋白参与调节各种细胞信号,其在伤口愈合中的作用尚不清楚。这里,我们已经确定了α-catenin/FAK/YAP信号轴在真皮成纤维细胞增殖和迁移中的关键作用,这有助于皮肤伤口愈合的过程。简而言之,当α-连环蛋白在真皮成纤维细胞中被特异性敲低时,伤口愈合速度明显延迟。此外,干扰α-catenin可以在体外和体内阻止真皮成纤维细胞的增殖和迁移。机械上,α-catenin的过表达上调了YAP的核积累和下游靶基因的转录,导致真皮成纤维细胞的增殖和迁移增强。此外,FAKTyr397磷酸化抑制剂阻断了α-catenin对YAP激活的促进作用。重要的是,FAKTyr397的连续磷酸化突变逆转了α-catenin敲低对伤口愈合的阻滞作用,通过增加成纤维细胞的活力。同样,α-连环蛋白/FAK被验证为db/db慢性创伤模型中伤口愈合的治疗靶标。总之,我们的发现揭示了α-catenin通过FAK/YAP信号轴的活性促进成纤维细胞功能的新机制。这些发现定义了加速伤口愈合过程的有希望的治疗策略。
Skin wound healing is a complex and organized biological process, and the dermal fibroblasts play a crucial role. α-Catenin is known to be involved in regulating various cellular signals, and its role in wound healing remains unclear. Here, we have identified the pivotal role of the α-catenin/FAK/YAP signaling axis in the proliferation and migration of dermal fibroblasts, which contributes to the process of skin wound healing. Briefly, when α-catenin was knocked down specifically in dermal fibroblasts, the wound healing rate is significantly delayed. Moreover, interfering with α-catenin can impede the proliferation and migration of dermal fibroblasts both in vitro and in vivo. Mechanistically, the overexpression of α-catenin upregulates the nuclear accumulation of YAP and transcription of downstream target genes, resulting in enhanced the proliferation and migration of dermal fibroblasts. Furthermore, the FAK Tyr397 phosphorylation inhibitor blocked the promoting effects of α-catenin on YAP activation. Importantly, the continuous phosphorylation mutation of FAK Tyr397 reversed the retardatory effects of α-catenin knockdown on wound healing, by increasing the vitality of fibroblasts. Likewise, α-catenin/FAK was validated as a therapeutic target for wound healing in the db/db chronic trauma model. In summary, our findings have revealed a novel mechanism by which α-catenin facilitates the function of fibroblasts through the activity of the FAK/YAP signaling axis. These findings define a promising therapeutic strategy for accelerating the wound healing process.