Netrin-4 Modulates Corneal Wound Healing by Enhancing Corneal Epithelium and Nerve Regeneration

Axon guidance proteins have been found to play a regenerative role in the peripheral nervous system and the cornea. Netrin-4 is a member of the Netrins family of axon guidance proteins implicated in diabetic retinopathy and corneal hemangiogenesis. However, its effects on corneal nerve and epithelium repair are not well understood. We performed in vitro and in vivo studies to assess the effects of Netrin-4 in corneal wound healing. We found that Netrin-4 induced extensive neurite growth and branching in trigeminal ganglia neurons and accelerated the scratch closure of corneal epithelial cells. In vivo, the dual action of Netrin-4 enhanced corneal epithelium healing and nerve regeneration in mice subjected to corneal epithelium debridement. Inhibition studies demonstrate that Netrin-4-induced neuronal growth may be mediated by interaction with Neogenin or α6β1 Integrin receptors. In conclusion, our data demonstrate that Netrin-4 has trophic and neuroregenerative effects in the cornea and could be a suitable therapeutic target to treat corneal injury.