Abstract
The ocular surface is covered by stratified squamous corneal epithelial cells that are in cell:cell contact with the axonal membranes of a dense collection of sensory nerve fibers that act as sentinels to detect chemical and mechanical injuries which could lead to blindness. The sheerness of the cornea makes it susceptible to superficial abrasions and recurrent erosions which demand continuous regrowth of the axons throughout life. We showed previously that topical application of the antibiotic and anticancer drug Mitomycin C (MMC) enhances reinnervation of the corneal nerves and reduces recurrent erosions in mice via an unknown mechanism. Here we show using RNA-seq and confocal imaging that wounding the corneal epithelium by debridement upregulates proteases and protease inhibitors within the epithelium and leads to stromal nerve disruption. MMC attenuates these effects after debridement injury by increasing serpine1 gene and protein expression preserving L1CAM on axon surfaces of reinnervating sensory nerves. These data demonstrate at the molecular level that gene expression changes in the corneal epithelium and stroma modulate sensory axon integrity. By preserving the ability of axons to adhere to corneal epithelial cells, MMC enhances sensory nerve recovery after mechanical debridement injury.
Highlights
Light passes through the cornea on its way to the retina
In response to 1.5 mm debridement injury, corneal epithelial cells migrate as a sheet; leading edge cells do not proliferate but cells at the corneal periphery increase their rate of proliferation[1]
To determine whether a single Mitomycin C (MMC) treatment at the time of debridement injury impacts reepithelialization and reinnervation, we first assess the area of the remaining wound 18 hr after wounding in standard of care treated wounded corneas (W) and in wounded corneas treated with MMC at the time of wounding (MW)
Summary
Light passes through the cornea on its way to the retina. The cornea functions as the primary refractive surface of the eye. Time of injury, we use RNA-seq transcriptomic analyses to determine the mechanisms underlying the ability of MMC to impact corneal wound resolution and ICN reinnervation Insights gained from these RNA-seq data allow us to demonstrate the involvement of secreted proteases in corneal axon homeostasis and reinnervation after injury and the importance of stromal nerve integrity in these processes. These data allow us to propose that MMC treatment of corneas with injuries that sever nerves but do not induce reepithelialization will delay reinnervation and we test the hypothesis experimentally. These data provide a rich resource to the community to understand how reepithelialization and reinnervation occur rapidly and efficiently in the cornea
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