Li Sanming, Zhou Jing, Bu Jinghua, Ning Ke, Zhang Liying, Li Juan, Guo Yuli, He Xin, He Hui, Cai Xiaoxin, Chen Yongxiong, Reinach Peter Sol, Liu Zuguo, Li Wei
From the Eye Institute of Xiamen University, Xiamen, Fujian 361102.
the Medical College of Xiamen University, Xiamen, Fujian 361102.
J Biol Chem. 2017 Aug 11;292(32):13391-13401. doi: 10.1074/jbc.M117.803809. Epub 2017 Jun 27.
The gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of mutant mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, EGFR, and ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis.
该基因编码外胚层发育不良蛋白A（Eda），如果发生突变，会导致人类X连锁少汗性外胚层发育不良（XLHED）疾病。XLHED患者会出现眼表变化，但其潜在机制仍不清楚。在本研究中，我们发现Eda在睑板腺中高度表达，且在人泪液中可检测到，但在血清中未检测到。突变小鼠出生后早期角膜上皮完整性存在缺陷且厚度减小。小鼠角膜上皮细胞增殖减少，上皮伤口愈合延迟，而外源性Eda可使其恢复。在器官培养过程中，Eda暴露促进小鼠角膜上皮伤口愈合，而划痕伤口试验表明它不影响人角膜上皮细胞系的迁移。小鼠角膜上皮中表皮生长因子受体（EGFR）、磷酸化EGFR（p-EGFR）和磷酸化ERK1/2（p-ERK）表达下调。Eda处理以剂量依赖方式上调人角膜上皮细胞中Ki67、EGFR、EGFR和ERK的表达。总之，Eda蛋白可从睑板腺分泌，并通过调节EGFR信号通路促进角膜上皮细胞增殖。Eda释放到泪液中对维持角膜上皮稳态起着至关重要的作用。
