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NGF Signaling in Innervation-dependent Corneal Epithelial Renewal: A Novel Approach to Neurotrophic Keratopathy Treatment
Arif Hussain MD1*, Kaveh Mirmoeini MD 2*, Chilando Mulenga B.S1, Jordan Crabtree B.S1, Kiana Tajdaran MD 2, Gregory Borschel MD1, Konstantin Feinberg PhD1
1. Department of Plastic Surgery at Indiana University School of Medicine
2. Program in Neuroscienc
2025-01-10
Presenter: Arif Hussain
Affidavit:
Gregory H. Borschel, MD
Gregory Borschel
Director Name: Gregory H. Borschel
Author Category: Fellow Plastic Surgery
Presentation Category: Basic Science Research
Abstract Category: Craniomaxillofacial
Background:
Corneal clarity is vital for vision, maintained by limbal stem cells (LSCs) at the corneal-conjunctival interface, where they interact with sensory nerves. Corneal nerves release trophic factors like nerve growth factor (NGF), which promotes epithelial renewal. Pathological denervation leads to Neurotrophic Keratopathy (NK), causing ulcers, scarring, and blindness, with limited treatment options. FDA-approved recombinant human NGF shows some efficacy but is costly and ineffective in 30% of cases. LSCs express NGF receptors TrkA and p75NTR, yet the mechanisms linking NGF signaling, sensory innervation, and epithelial renewal remain unclear. We hypothesize that NGF regulates LSC-driven epithelial renewal via differential receptor activation.
Methods:
We performed in vivo studies using wild-type rats and mutant mice to investigate the role of NGF signaling in corneal epithelial renewal mediated by innervation. Our experiments evaluated the impact of various combinations of TrkA and p75NTR agonists and antagonists on the healing of experimentally wounded corneas, both with intact innervation and after surgical denervation.
Results:
Inactivation of TrkA fully blocks the healing process in normally innervated corneas. However, when p75NTR is inhibited and a single daily dose of NGF is administered, denervated de-epithelialized corneas undergo rapid and complete healing.
Conclusions:
The expression of NGF and its precursor, proNGF, by corneal sensory nerves regulates LSC proliferation and differentiation through selective activation of NGF receptors. A combined approach of TrkA activation and p75NTR inhibition will be utilized to develop an enhanced NGF-based therapy for treating NK.
