Wang Jingrao, Zhu Rui, Dong Yueyan, Feng Jiaoyang, Gao Jingfan, Wang Shu, Lin Jia, Li Yulin, Du Weijie, Jin Xin, Zhang Hong
Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Key Laboratory of Basic and Clinical Research of Heilongjiang Province, Harbin, Heilongjiang Province, People's Republic of China; NHC Key Laboratory of Cell Transplantation, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Key Laboratory of Basic and Clinical Research of Heilongjiang Province, Harbin, Heilongjiang Province, People's Republic of China.
Int J Biol Macromol. 2025 Jan;285:138267. doi: 10.1016/j.ijbiomac.2024.138267. Epub 2024 Dec 2.
Corneal complications associated with diabetes are gradually receiving attention because of the large number of patients with diabetes. The current treatment for diabetic corneal lesions relies on symptomatic relief, which has uncertain efficacy. Exploring the mechanisms underlying delayed corneal epithelial healing in diabetes is of great significance for the treatment of this disease. N6-methyladenosine (m6A), the most common modification of RNA, plays a key role in a range of diseases. Nevertheless, the role and mechanisms underlying m6A regulation in diabetic corneal epithelial wound healing have not yet been elucidated. Here, we found that thrombospondin 2 (THBS2) was downregulated in the corneas of diabetic mice using m6A-mRNA and lncRNA epitranscriptomic microarrays. Overexpression of THBS2 promoted the proliferation and migration of human corneal epithelial cells (HCECs) by activating the Wnt/β-catenin signaling pathway. Enforced THBS2 expression promoted corneal epithelial wound healing in diabetic mice. Moreover, we found that the m6A reader protein YTH domain family protein 3 (YTHDF3) was downregulated at the mRNA and protein levels in the corneas of both diabetic mice and HCECs treated with glycation end products. YTHDF3 knockdown delayed corneal epithelial wound healing in diabetic mice. Mechanistically, YTHDF3 promoted THBS2 translation by recognizing m6A sites in the coding region of THBS2. Collectively, our findings indicate that THBS2 plays a vital role in regulating corneal epithelial wound healing, and targeting the YTHDF3/THBS2 axis could offer a potential therapeutic strategy for treating delayed corneal epithelial wound healing.
由于糖尿病患者数量众多，与糖尿病相关的角膜并发症逐渐受到关注。目前糖尿病角膜病变的治疗依赖于症状缓解，但其疗效尚不确定。探索糖尿病中角膜上皮愈合延迟的潜在机制对该病的治疗具有重要意义。N6-甲基腺苷（m6A）是RNA最常见的修饰，在一系列疾病中起关键作用。然而，m6A调控在糖尿病角膜上皮伤口愈合中的作用和机制尚未阐明。在此，我们使用m6A-mRNA和lncRNA表观转录组微阵列发现糖尿病小鼠角膜中的血小板反应蛋白2（THBS2）表达下调。THBS2的过表达通过激活Wnt/β-连环蛋白信号通路促进人角膜上皮细胞（HCEC）的增殖和迁移。强制表达THBS2可促进糖尿病小鼠角膜上皮伤口愈合。此外，我们发现m6A阅读蛋白YTH结构域家族蛋白3（YTHDF3）在糖尿病小鼠角膜以及用糖基化终产物处理的HCEC的mRNA和蛋白水平均下调。敲低YTHDF3会延迟糖尿病小鼠角膜上皮伤口愈合。机制上，YTHDF3通过识别THBS2编码区的m6A位点促进THBS2的翻译。总的来说，我们的研究结果表明THBS2在调节角膜上皮伤口愈合中起关键作用，靶向YTHDF3/THBS2轴可能为治疗延迟的角膜上皮伤口愈合提供一种潜在的治疗策略。
