Abstract
Topical application of vascular endothelial growth factor A (VEGFA) inhibitors including Bevacizumab is used for antiangiogenic therapy at the ocular surface. While clinical studies have suggested that this approach is well-tolerated, the effect of the drug on limbal epithelial stem cells has not been studied. In this study, the effect of Bevacizumab on phenotype and functionality of putative limbal epithelial stem cells (SC) was investigated. The effect of Bevacizumab on human limbal epithelial cells was assessed in terms of metabolic activity and scratch wound closure. The different treatment groups featured no difference in proliferation and colony forming efficiency (CFE) of limbal epithelial cells or their putative SC marker expression. A significant delay in scratch closure of all the Bevacizumab-treated groups was detected at 4 h. RNA and protein quantification indicated a dose-responsive increase of keratin 3. VEGFA RNA expression also increased while VEGFC and D as well as VEGFR1, 2 and 3 were unchanged. This study highlights previously unknown effects of Bevacizumab on cultured putative limbal epithelial SC: a dose-related increase of keratin 3, an increase in VEGFA as well as a delay in scratch wound closure. These in vitro data should be considered when using Bevacizumab in the context of limbal epithelial SC transplantation.
Highlights
Corneal avascularity and transparency are essential for normal vision
In addition to proliferation and wound healing assessment, we have investigated the effect of Bevacizumab on the putative limbal epithelial stem cell phenotype
This study on the in vitro effects of Bevacizumab on putative limbal epithelial stem cells shows that Bevacizumab treatment causes a delay in scratch wound closure
Summary
Corneal avascularity and transparency are essential for normal vision. Absence of corneal blood and lymphatic vessels is mediated by a delicate network of inhibitory mechanisms in the cornea [1]. An intact corneal epithelium is necessary for transparency and refraction [2]. This epithelial layer is constantly replenished by a limbal epithelial stem cell (LESC) population residing in the basal epithelial layer of the limbus [3,4]. Dysfunction or depletion of limbal epithelial cells (limbal stem cell deficiency, LSCD) results in persistent corneal inflammation, corneal surface conjunctivalization, corneal neovascularization and recurrent epithelial defects [5,6]. Conditions leading to LSCD and neovascularization are chemical and thermal burns, inflammatory eye diseases, persistent hypoxia (contact lens wear) [7] as well as genetic disorders such as aniridia [8]. Patients with LSCD suffer from photophobia, reduced visual acuity and pain due to recurrent ocular surface defects. LSCD can result to blindness [4]
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