Limbal Epithelial Stem Cells in the Diabetic Cornea

Abstract

Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the limbus. In patients afflicted with diabetes, hyperglycemia-induced impairments in corneal epithelial regeneration results in persistent epithelial and other defects on the ocular surface, termed diabetic keratopathy (DK), which progressively diminish vision and quality of life. Reports of delayed corneal wound healing and the reduced expression of putative stem cell markers in diabetic relative to healthy eyes suggest that the pathogenesis of DK may be associated with the abnormal activity of LESCs. However, the precise role of these cells in diabetic corneal disease is poorly understood and yet to be comprehensively explored. Herein, we review existing literature highlighting aberrant LESC activity in diabetes, focusing on factors that influence their form and function, and emerging therapies to correct these defects. The consequences of malfunctioning or depleted LESC stocks in DK and limbal stem cell deficiency (LSCD) are also discussed. These insights could be exploited to identify novel targets for improving the management of ocular surface complications that manifest in patients with diabetes.

The Role of Insulin-like Growth Factor (IGF) System in the Corneal Epithelium Homeostasis—From Limbal Epithelial Stem Cells to Therapeutic Applications

“…Microarray analysis demonstrated that among the 29 miRNA studied, miR-146a, 21, and 424 were the most upregulated, while miR-509-3p and 143 were expressed at the lowest level. This is in line with other reports, which indicate that overexpression of miR-146a in the diabetic limbus may result in a reduced corneal inflammatory and healing response [ 24 , 93 , 94 ]. In another study, genome-wide sequencing was applied, identifying differences in expression profiles of 20 miRNA between normal and diabetic human corneas [ 95 ].…”

“…A fundamentally negative impact of diabetes on the corneal epithelium is closely linked to its effect on LESC functioning [ 24 ]. A significant reduction in Palisades of Vogt in all four limbus quadrants was demonstrated in patients with type 2 diabetes using in vivo confocal microscopy [ 65 ].…”

“…A study employing a new method of objective quantification of immunofluorescence, aiming to overcome limitations of manual grading, observed a reduction in the putative LESC marker K14 in the limbus of diabetic mice [ 24 ]. Furthermore, reduced expression of putative limbal epithelial stem cell markers, such as paired box protein-6 (PAX6), ∆Np63α, K15, K17, and membrane transporter ABCG2, was demonstrated in cultured diabetic human limbal epithelial cells, which was associated with slower corneal epithelial wound healing [ 29 ].…”

“…Furthermore, reduced expression of putative limbal epithelial stem cell markers, such as paired box protein-6 (PAX6), ∆Np63α, K15, K17, and membrane transporter ABCG2, was demonstrated in cultured diabetic human limbal epithelial cells, which was associated with slower corneal epithelial wound healing [ 29 ]. It is crucial to note, however, that several cell markers for LESCs can also be identified in other parts of the eye, and their use has limitations in discriminating pure stem cells from early transient amplifying cells [ 24 , 66 ].…”

“…This overactivation led to dysfunction and reduced proliferation of limbal stem/progenitor cells in response to a chemical injury. Additionally, the interplay between the nervous and immune system may impact limbal stem cells [ 24 , 86 ]. Immune cells residing in the cornea, such as T cells, interact with dendritic corneal cells and sensory nerves, influencing a response to acute and chronic stimuli [ 87 ].…”