Zhao Huan-Yu, Jiang Jie-Bing, Chen Yu, Miao Chao-Yu
Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai 200433, China.
Department of Gynecology and Obstetrics, The First Affiliated Hospital (Changhai Hospital), Second Military Medical University/Naval Medical University, Shanghai 200433, China.
Pharmaceuticals (Basel). 2025 Aug 10;18(8):1180. doi: 10.3390/ph18081180.
Metrnl (Meteorin-like), a secreted protein identified in our lab, has been shown to promote wound healing in mice. However, current therapeutic strategies and the underlying mechanisms remain incompletely understood. This study aimed to (1) develop a recombinant human Metrnl (hMetrnl) hydrogel formulation for topical delivery, and (2) elucidate its molecular mechanism in wound repair. hMetrnl was dispersed in a thermosensitive PLGA-PEG-PLGA hydrogel (hMet-PPP) and applied topically to full-thickness skin wounds in male C57BL/6 mice. A large initial dose was administered on the day of injury, followed by a lower maintenance dose regimen. Mechanistic studies were performed using molecular/cellular assays to assess the effects of hMetrnl. Administration of hMet-PPP significantly accelerated wound healing, reducing the initial wound area and shortening the overall recovery time. hMetrnl transmits signals to endothelial cells via the KIT receptor tyrosine kinase (C-Kit), a membrane receptor, thereby initiating a dual regulatory mechanism involving eNOS to promote angiogenesis: (1) rapid activation of eNOS activity within 30 min through the PI3K/AKT signaling pathway; and (2) suppression of proteasomal and lysosomal eNOS degradation, resulting in enhanced eNOS expression and prolonged functional activity under sustained treatment. Topical hMet-PPP administration represents a promising therapeutic strategy for enhancing early-stage wound healing. hMetrnl exerts its biological effects through C-Kit, which mediates dual regulation of eNOS, both activation and stabilization, providing a mechanistic basis for its potent angiogenic properties. These findings uncover a novel Metrnl mechanism with potential implications for the development of therapies targeting vascular dysfunction and tissue repair.
Metrnl（类气象素）是我们实验室鉴定出的一种分泌蛋白，已被证明可促进小鼠伤口愈合。然而，目前的治疗策略及其潜在机制仍未完全明确。本研究旨在：（1）开发一种用于局部递送的重组人Metrnl（hMetrnl）水凝胶制剂；（2）阐明其在伤口修复中的分子机制。将hMetrnl分散在热敏性聚乳酸-羟基乙酸共聚物-聚乙二醇-聚乳酸-羟基乙酸共聚物水凝胶（hMet-PPP）中，并局部应用于雄性C57BL/6小鼠的全层皮肤伤口。在受伤当天给予大剂量初始剂量，随后采用较低的维持剂量方案。使用分子/细胞分析方法进行机制研究，以评估hMetrnl的作用。给予hMet-PPP可显著加速伤口愈合，减小初始伤口面积并缩短总体恢复时间。hMetrnl通过膜受体KIT受体酪氨酸激酶（C-Kit）向内皮细胞传递信号，从而启动涉及内皮型一氧化氮合酶（eNOS）的双重调节机制以促进血管生成：（1）通过磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）信号通路在30分钟内快速激活eNOS活性；（2）抑制蛋白酶体和溶酶体对eNOS的降解，导致在持续治疗下eNOS表达增强且功能活性延长。局部给予hMet-PPP是增强早期伤口愈合的一种有前景的治疗策略。hMetrnl通过C-Kit发挥其生物学作用，C-Kit介导eNOS的双重调节，即激活和稳定，为其强大的血管生成特性提供了机制基础。这些发现揭示了一种新的Metrnl机制，对针对血管功能障碍和组织修复的治疗方法的开发具有潜在意义。
