Ma David Hui-Kang, Chen Jan-Kan, Zhang Fen, Lin Kuei-Ying, Yao Jeng-Yuan, Yu Jau-Song
Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
Prog Retin Eye Res. 2006 Nov;25(6):563-90. doi: 10.1016/j.preteyeres.2006.09.001. Epub 2006 Oct 31.
Corneal angiogenesis is associated with a variety of corneal diseases, and is sometimes vision threatening. In recent years, with the discovery of major pro- and anti-angiogenic factors in the cornea, details of the angiogenic process are gradually unveiled. Of note, corneal inflammation and neovascularization associated with severe limbal stem cell (LSC) deficiency is a clinically challenging issue in that the condition persists long after the initial insult, and will not improve without transplantation of LSCs. However, to date the molecular mechanism by which LSC transplantation restores corneal avascularity is not fully understood. In addition to discussing major pro-angiogenic factors involved in corneal neovascularization, this review article also focuses on possible molecular mechanisms underlying persistent inflammation and neovascularization following severe LSC deficiency, and anti-angiogenic factors expressed by human limbo-corneal epithelial cells (HLCECs). Most of the recently discovered corneal anti-angiogenic factors belong to extracellular matrix proteins that acquire angio-inhibitory activity only after proper proteolytic processing. Our recent findings showed that the secretion of endostatin (derived from basement membrane collagen XVIII) and restin (from collagen XV) by HLCECs were enhanced when HLCECs were cultivated on amniotic membrane (AM). This adds to the advantage of transplanting ex vivo expanded HLCECs cultivated on AM in that the anti-angiogenic activity of the epithelial cells is augmented in a physiological way. Furthermore, proteomic profiling of HLCECs and human conjunctival epithelial cells (HCECs) identified a 14-3-3 protein (stratifin) preferentially expressed by HLCECs. In addition to functioning as a cell cycle controller, keratinocyte-derived stratifin induces MMPs which are involved in the generation of restin (by MMP-1) and endostatin (by MMP-3). These findings highlight the significance of delicate epithelial-matrix interactions in the maintenance of corneal avascularity.
角膜血管生成与多种角膜疾病相关，有时会威胁视力。近年来，随着角膜中主要促血管生成因子和抗血管生成因子的发现，血管生成过程的细节逐渐被揭示。值得注意的是，与严重角膜缘干细胞（LSC）缺乏相关的角膜炎症和新生血管形成是一个临床难题，因为这种情况在初次损伤后会持续很长时间，并且在不进行LSC移植的情况下不会改善。然而，迄今为止，LSC移植恢复角膜无血管状态的分子机制尚未完全了解。除了讨论参与角膜新生血管形成的主要促血管生成因子外，本文还重点关注严重LSC缺乏后持续炎症和新生血管形成的可能分子机制，以及人角膜缘角膜上皮细胞（HLCEC）表达的抗血管生成因子。最近发现的大多数角膜抗血管生成因子属于细胞外基质蛋白，只有经过适当的蛋白水解加工后才获得血管抑制活性。我们最近的研究结果表明，当HLCEC在羊膜（AM）上培养时，其内皮抑素（源自基底膜胶原蛋白XVIII）和restin（源自胶原蛋白XV）的分泌会增加。这增加了移植在AM上培养的体外扩增HLCEC的优势，因为上皮细胞的抗血管生成活性以生理方式增强。此外，HLCEC和人结膜上皮细胞（HCEC）的蛋白质组分析确定了一种14-3-3蛋白（层粘连蛋白）优先由HLCEC表达。除了作为细胞周期控制器发挥作用外，角质形成细胞衍生的层粘连蛋白还诱导参与restin（由MMP-1产生）和内皮抑素（由MMP-3产生）生成的基质金属蛋白酶（MMP）。这些发现突出了精细的上皮-基质相互作用在维持角膜无血管状态中的重要性。
