Vision loss caused by diabetes arises primarily from retinopathy, but up to 70% of people with diabetes also experience corneal problems, including keratopathy and neuropathy. Diabetic keratopathy involves impairments in epithelial wound healing, barrier function, and tear production, along with epithelial erosions and keratitis. As a result, the cornea may heal more slowly and less completely following an injury or procedures such as cataract surgery or laser therapy for diabetic retinopathy.
The abnormal wound healing is caused by impaired limbal epithelial stem cells, and the new research, published online in Diabetologia, involved isolation of those cells from 30 donor eyes of humans with and 23 without diabetes. Significant differences were found in DNA methylation between the cells of those two groups. Specifically, the WNT5A gene was hypermethylated at the promotor region in the diabetic cells and its protein markedly repressed.
However, treatment with various approaches, including exogenous WNT5A methylation inhibitors and a nanoconjugate that inhibits WNT5A suppression, improved corneal epithelial wound healing as well as expression of the limbic epithelial stem cells.
“Overall, [the] Wnt-5a [protein] is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea,” wrote Ruchi Shah, PhD, of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, and colleagues.
The finding represents more cellular changes than researchers had previously been aware of, study senior author Alexander Ljubimov, PhD, DSc, director of the eye program at the Institute, said in a statement.
“The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression – what are known as epigenetic alterations,” he said.
In the experiments, treatment of the impaired diabetic limbal epithelial cells with the exogenous Wnt-5a accelerated wound healing by 1.4-fold (P < .05), compared with untreated cells and reduced healing time in diabetic organ-ultured corneas by 37% (P < .05).
Treatment with the DNA methylation inhibitor zebularine also increased levels of Wnt-5a in the diabetic limbic epithelial cells by 37% (P < .01), dose-dependently stimulated wound healing by 60% at 24 hours (P < .01), and improved wound healing by 30% in diabetic organ-cultured corneas.
The finding of Wnt-5a as a new diabetic corneal marker regulating wound healing and stem cell function may have implications for other diabetes complications involving impaired wound healing, including diabetic foot ulcers, as they share similar neurovascular, sensory, and immunological compromise with diabetic eye disease, Dr. Shah and colleagues wrote.
“Novel therapies to reverse both types of epigenetic silencing could benefit corneal function and may also prove to be beneficial in other wound healing–related diabetic complications,” they wrote.
The investigators are now working on combination therapies that target both mRNA and DNA methylation in hopes of obtaining even better wound healing.
“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Dr. Ljubimov. “Drugs that are [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”
This work was funded by the National Institutes of Health and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. The authors reported no further disclosures.
A version of this article appeared on Medscape.com.