Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo, Japan.
Eur Rev Med Pharmacol Sci. 2024 Feb;28(3):949-958. doi: 10.26355/eurrev_202402_35332.
Wound repair dysfunction is becoming a major public health issue worldwide. Yes-associated protein (YAP) has previously been reported to be closely related to wound healing, while how YAP accelerates wound healing via regulating autophagy needs to be further probed.
ICR male mice were involved in two independent animal experiments; the mice were randomly allocated into control, autophagy inhibitor (3-MA) (injection), and 3-MA (drip) group or control, si-NC, si-YAP group (8 mice for each). Full-thickness excisional wounds (8 mm) in mice were created by punch to construct an in vivo wound model to observe the effects of autophagy inhibitor (3-MA) (by injection and drip) and si-YAP by electrotransfection.
Firstly, we found that the autophagy inhibitor (3-MA) accelerated wound closure in vivo. Loss-of-function experiments subsequently revealed that YAP knockdown led to increased proliferation and migration of fibroblasts as well as reduced autophagy, resulting in accelerated wound healing. In addition, our results revealed that YAP could positively regulate Engrailed-1 (En1) expression in fibroblasts. En1 knockdown also promoted the proliferation and migration of fibroblasts, meanwhile resulting in increased mammalian target of rapamycin (mTOR) levels and reduced autophagy in fibroblasts.
YAP knockdown repressed autophagy in fibroblasts to accelerate wound closure by regulating the En1/mTOR axis.
伤口修复功能障碍正在成为全球主要的公共卫生问题。Yes 相关蛋白（YAP）先前被报道与伤口愈合密切相关，而 YAP 通过调节自噬加速伤口愈合的机制仍需进一步研究。
本研究纳入了两项独立的动物实验，ICR 雄性小鼠被随机分配至对照组、自噬抑制剂（3-MA，注射）组和 3-MA（滴注）组，或对照组、si-NC 组、si-YAP 组（每组 8 只小鼠）。通过打孔法构建小鼠全层皮肤切除创面（8mm）的体内创面模型，观察自噬抑制剂（3-MA，注射和滴注）和电转染 si-YAP 的作用。
首先，我们发现自噬抑制剂（3-MA）可加速体内创面闭合。随后的功能丧失实验表明，YAP 敲低导致成纤维细胞增殖和迁移增加，自噬减少，从而加速伤口愈合。此外，我们的结果表明 YAP 可正向调节成纤维细胞中的 Engrailed-1（En1）表达。En1 敲低也促进了成纤维细胞的增殖和迁移，同时导致成纤维细胞中哺乳动物雷帕霉素靶蛋白（mTOR）水平升高和自噬减少。
YAP 敲低通过调节 En1/mTOR 轴抑制成纤维细胞中的自噬，从而加速创面闭合。
