Grants Funded

Abstract

Project Summary: Overview: Limbal stem cells (LSCs), the source of the corneal epithelial cells, are located in the basal epithelium of the limbus, where they interact with corneal sensory nerves. Besides their protective role, the corneal nerves are thought to stimulate LSC activity. If the cornea is denervated, corneal ulcers, scarring, and opacification occur due to repetitive wounding and failure to heal. This condition, termed Neurotrophic Keratopathy (NK), is a major cause of corneal blindness. Historically there is no cure for NK; even corneal transplants inevitably fail due to the lack of innervation. Preliminary studies: The molecular mechanisms underlying the role of the nerves in LSC activity is poorly understood. By combining surgical manipulations, single cell expression analysis (scRNA-seq) and locally-induced selective cell ablation, we defined corneal nerves-associated Schwann cells (SCs) as a component of LSCs niche, serving as “paracrine factories”, vital for corneal wound healing, epithelial maintenance and ocular surface health. We have further observed that several SC-expressed topical trophic factors induce corneal epithelial renewal and prevent development of NK in animal models. Innovation: In the proposed research we will (i) in a gain-of-function experiment, define the critical role of SCs in corneal epithelial renewal, (ii) define pleiotrophin (PTN) as a novel and critical cytokine involved in SC-mediated corneal epithelial renewal, (iii) define the role and the extent to which PTN together with ciliary neurotrophic factor (CNTF) stimulates LSCs activity and (iv) develop new comprehensive topical therapeutic strategies for NK. Summary: The studies in this proposal will provide mechanistic understanding of regulation of LSC activity by SC during corneal epithelial renewal. This knowledge will be leveraged clinically in the development of topical therapeutics for NK complementing existing surgical approaches or substituting for surgery altogether.

Impact Statement: Clarity of the cornea is essential for vision. Corneal sensory innervation protects the cornea from injury and stimulates corneal epithelial renewal. Deficits in corneal sensory innervation cause Neurotrophic Keratopathy (NK) and ultimately leads to irreversible blindness. The existing therapeutic approaches are moderately effective, often non affordable and, as in case of surgical corneal “neurotization” treatment, associated with a limited accessibility and long recovery. We aim to develop adjunctive topical therapeutics for NK, based on defining the indigenous intercellular interactions regulating innervation-dependent corneal epithelial renewal. Such treatment will improve the results of surgery and perhaps replace surgery altogether, thus restoring vision to millions of people.

Biography
Konstantin Feinberg, PhD, Assistant Research Professor of Surgery at the IU School of Medicine, is trained as a biochemist and molecular neurobiologist, with special emphasis on ligand-receptor interactions and cellular communication in the nervous system. As a co-PI with Dr. Borschel, Dr. Feinberg’s research focuses on the role of the corneal sensory innervation in regulation of Limbal Stem Cell-dependent corneal epithelial renewal. This research has led to the recently reported discovery of corneal nerves-associated Schwann cells as a novel key component of the limbal niche, mediating the epithelial renewal (Mirmoeini et al., 2023 IOVS). During his graduate studies, Dr. Feinberg has identified NrCAM as a glial protein that, together with gliomedin, induces the clustering of sodium channels. Further, he discovered the clues behind node of Ranvier formation in the peripheral nervous system (Feinberg et al., 2010 Neuron). During his postdoctoral training, he developed a method to generate functional Schwann cells from human skin-derived mesenchymal stem cells and demonstrated their potential to re-myelinate in a sciatic nerve injury rat model. During his postdoctoral fellowship, Dr. Feinberg repurposed a potent neuroprotective drug for use as a therapeutic agent for nerve injuries and neurodegeneration. He used this drug to identify a previously unknown pro-degenerative feature of the NGF receptor TrkA in sympathetic and sensory neurons (Feinberg et al., 2018 JCB).