SO9. New Hope For Patients With Neurotrophic Keratopathy: Molecular Interactions Governing Nerve-mediated Control Of Corneal Epithelial Renewal And Wound Healing

Abstract

PURPOSE: Corneal clarity, essential for vision, is maintained by limbal stem cells (LSCs), which generate transparent limbal epithelial cells. Corneal sensory nerves, beyond their protective role, are believed to stimulate LSCs via unknown mechanisms. Neurotrophic keratopathy (NK), caused by absent corneal innervation from congenital or acquired etiologies (e.g., tumors, trauma, infections), leads to blindness. Corneal nerve-associated Schwann cells (SCs) play a crucial role in wound healing and epithelial maintenance. Our scRNA-seq studies suggest that several trophic factors secreted by SCs regulate LSC activity, identifying pleiotrophin (PTN) as a novel SC-derived regulator of corneal renewal, particularly when combined with ciliary neurotrophic factor (CNTF). METHODS: In our two NK models, either local ablation of SC or surgical corneal denervation causes corneal ulceration and prevents healing of experimental corneal ulcers. To define the role of PTN in corneal epithelial renewal, we tested the effects of topical recombinant PTN alone or with other trophic factors on the healing of surgically denervated or genetically SC-ablated deepithelialized rodent corneas. RESULTS: (i) PTN alone induced rapid healing, and, (ii) when applied together with (CNTF), induced complete recovery of corneal clarity. CONCLUSION: Under conditions of denervation or SC loss, exogenous PTN with CNTF rescue corneal epithelial renewal. These findings will be leveraged towards the development of topical treatments for NK.