Abstract：
The cornea fends off chemicals, dirt, and infectious particles and provides most of the eye\'s focusing power. Corneal transparency is of paramount importance to normal vision, yet how it is established and maintained remains unclear. Here, we ablated Notch1 in keratocytes using Twist2-Cre mice and found that Twist2-Cre; Notch1f/f mice developed stroma expansion and neovascularization, followed by hyperproliferation and metaplasia of corneal epithelial progenitor cells and plaque formation at central cornea, leading to loss of transparency. Development of these phenotypes does not involve bacteria-caused inflammation; instead, Notch1 deletion upregulates Vegfa and Vegfc via Hif1α in keratocytes. Vascular endothelial growth factor (VEGF) receptor inhibitor axitinib prevented development of these anomalies in Twist2-Cre; Notch1f/f mice, suggesting that VEGFs secreted by keratocytes promote not only neovascularization but also proliferation and metaplasia of epithelial progenitor cells at central cornea. This study uncovers a Notch1-Hif1α-VEGF pathway in keratocytes that maintains corneal transparency and represents a potential target for treatment of related corneal disorders.
摘要：
角膜抵御化学物质，污垢,和传染性粒子，并提供大部分的眼睛的聚焦能力。角膜透明度对正常视力至关重要，然而，它是如何建立和维持的仍不清楚。这里,我们使用Twist2-Cre小鼠在角膜细胞中消融Notch1，发现Twist2-Cre;Notch1f/f小鼠发生基质扩张和新生血管形成，其次是角膜上皮祖细胞的过度增殖和化生以及中央角膜的斑块形成，导致透明度的丧失。这些表型的发展不涉及细菌引起的炎症；相反，Notch1缺失通过Hif1α在角膜细胞中上调Vegfa和Vegfc。血管内皮生长因子（VEGF）受体抑制剂阿西替尼预防Twist2-Cre;Notch1f/f小鼠，提示角膜上皮细胞分泌的VEGF不仅促进角膜中央上皮祖细胞的新生血管形成，而且促进上皮祖细胞的增殖和化生。这项研究揭示了角膜细胞中Notch1-Hif1α-VEGF通路，该通路可保持角膜透明度，并代表了治疗相关角膜疾病的潜在靶标。
