Song Lingyu, Chang Xuebing, Hu Laying, Liu Lu, Wang Guifang, Huang Yali, Xu Lifen, Jin Bangming, Song Jianying, Hu Lixin, Zhang Tian, Wang Yuanyuan, Xiao Ying, Zhang Fan, Shi Mingjun, Liu Lingling, Chen Qi, Guo Bing, Zhou Yuxia
Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou, China.
Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
Diabetes. 2023 Nov 1;72(11):1692-1706. doi: 10.2337/db23-0173.
Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like [Metrnl]) accelerates wound epithelialization and angiogenesis in mice. We observed a significant increase in Metrnl expression during physiological wound healing; however, its expression remained low during diabetic wound healing. Functionally, the recombinant protein Metrnl significantly accelerated wound closure in normal and diabetic mice models including db/db, high-fat diet/streptozotocin (HFD/STZ), and STZ mice. Mechanistically, keratinocytes secrete quantities of Metrnl to promote angiogenesis; increase endothelial cell proliferation, migration, and tube formation; and enhance macrophage polarization to the M2 type. Meanwhile, M2 macrophages secrete Metrnl to further stimulate angiogenesis. Moreover, the keratinocyte- and macrophage-produced cytokine Metrnl drives postinjury angiogenesis and reepithelialization through activation of AKT phosphorylation (S473) in a KIT receptor tyrosine kinase (c-Kit)-dependent manner. In conclusion, our study suggests that Metrnl has a biological effect in accelerating wound closure through c-Kit-dependent angiogenesis and epithelialization.
伤口愈合受损和溃疡并发症是糖尿病患者发病的主要原因。糖尿病患者伤口愈合受损与炎症增加和血管生成不良有关。在此，我们证明局部应用一种分泌型重组蛋白（类 Meteorin [Metrnl]）可加速小鼠伤口上皮化和血管生成。我们观察到在生理性伤口愈合过程中 Metrnl 表达显著增加；然而，在糖尿病伤口愈合过程中其表达仍保持较低水平。在功能上，重组蛋白 Metrnl 在包括 db/db、高脂饮食/链脲佐菌素（HFD/STZ）和 STZ 小鼠在内的正常和糖尿病小鼠模型中显著加速伤口闭合。机制上，角质形成细胞分泌大量 Metrnl 以促进血管生成；增加内皮细胞增殖、迁移和管腔形成；并增强巨噬细胞向 M2 型极化。同时，M2 巨噬细胞分泌 Metrnl 以进一步刺激血管生成。此外，角质形成细胞和巨噬细胞产生的细胞因子 Metrnl 通过以 KIT 受体酪氨酸激酶（c-Kit）依赖的方式激活 AKT 磷酸化（S473）来驱动损伤后血管生成和再上皮化。总之，我们的研究表明 Metrnl 通过 c-Kit 依赖的血管生成和上皮化对加速伤口闭合具有生物学作用。
