Optometry and Vision Sciences - Theses
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ItemNeuroregenerative and anti-inflammatory effects of decorin on the injured cornea( 2022)The cornea is densely innervated by sensory nerves that responds to noxious stimuli and produces neurotrophic factors to maintain ocular surface homeostasis. However, corneal sensory nerves are susceptible to damage from a range of ocular and systemic conditions, including dry eye disease, corneal infection, trauma, surgical procedures and diabetes mellitus. Despite corneal nerve impairment being a key pathophysiologic factor in many ocular surface diseases, there are few effective therapeutic approaches to promote corneal nerve regeneration. Decorin is an extracellular matrix protein that belongs to a family of small leucine-rich proteoglycans. Decorin interacts with different signaling molecules to regulate various cellular processes including collagen fibrillogenesis, fibrosis, inflammation and axon growth. There is evidence that decorin is of great potential as a therapeutic for treating spinal cord injury to suppress the formation of a glial scar and promote axon growth. Here, it is hypothesized that exogenous decorin may provide therapeutic benefits in peripheral nerve damage in corneal neuropathy. This thesis aims to explore the neuroregenerative and anti-inflammatory effects of decorin on the injured cornea and to verify its therapeutic potential to restore corneal homeostasis after corneal nerve injury. To assess this, corneal nerve damage was modelled in mice by direct abrasion of the central epithelium. Decorin or vehicle was applied topically after the injury and wholemount immunofluorescence staining was used to assess corneal sensory nerves and immune cell densities. Topical decorin treatment was associated with a higher density of corneal sensory nerves, relative to topical vehicle (control) treatment. This neuroregenerative effect of decorin was not observed in Cx3cr1gfp/gfp mice that spontaneously lack corneal epithelial dendritic cells (DCs), indicating that decorin-induced corneal nerve regeneration depends on the presence of DCs. In addition, topical decorin induced a higher density of DCs after six hours, and a lower density of macrophages at one week post-injury, supporting a role for decorin in modulating corneal immune responses. To further investigate the immunomodulatory effect of decorin during corneal wound healing, the same model was used to evaluate the temporal changes to corneal immune cells at multiple timepoints, including 12 hours, 24 hours, 3 days and 5 days post-injury. After topical decorin application, a higher density of corneal epithelial DCs and a lower density of infiltrating neutrophils were observed at 24 hours after injury. The decorin-induced lower neutrophil density was also DC-dependent. Consistent with the previous study, corneal stromal macrophage density was lower and corneal nerve density was higher in decorin-treated eyes compared to saline-treated controls. Interestingly, a higher percentage of the injured corneal area was re-epithelialized in decorin-treated eyes at 12 hours post-injury. These findings confirmed the neuroregenerative effect of decorin and demonstrated a distinctive pattern of temporal dynamics of corneal immune cells that were modulated by topical decorin. These effects of topical decorin on the injured cornea were associated with altered expression of transforming growth factor beta and chondroitin sulfate proteoglycan 4 signaling mRNA. In addition to evaluating an acute epithelial injury, repeated exposure to a corneal neuro-toxic stimulus was also considered, as this is not uncommon in clinical settings (e.g., in patients with long-term use of preservative-containing eye drops). Therefore, the therapeutic effects of decorin were also investigated in an animal model of chemical-induced corneal neuropathy, with repeated topical exposure to a common preservative benzalkonium chloride (BAK). Topical decorin treatment was also applied during a one-week period of daily BAK exposure. This study showed that decorin-treated eyes had less corneal neutrophil infiltration and a lower density of macrophages, accompanied by a higher density of corneal sensory nerves. In addition, corneal nerve density was negatively correlated with macrophage and neutrophil density, indicating that alterations to corneal immune cells induced by decorin may contribute to a higher density of sensory nerves. Together, these findings advance understanding of the relationship between corneal sensory nerves and immune cells, and more importantly, provide evidence for the therapeutic potential of topical decorin in conditions characterized by corneal nerve damage with local inflammation.