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Schwann cells are required for efficient corneal wound healing
Kaveh Mirmoeini, MD, MASc1, Konstantin Feinberg, PhD2, Kiana Tajdaran, MD, MASc1, Jennifer Zhang, MD, PhD3, Tessa Gordon, PhD4, Asim Ali, BA.Sc., MD, FRCSC5 and Gregory H. Borschel, MD4, (1)University of Toronto, Toronto, ON, Canada, (2)Riley Hospital for Children, Indianapolis, IN, (3)The hospital for sick children, Toronto, ON, Canada, (4)Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada, (5)University of Toronto/ The Hospital for Sick Childeren, Toronto, ON, Canada

Background: Corneal nerves play a crucial role in maintaining corneal health, which includes regulation of activity of limbal stem cell (LSC). Their loss leads to neurotrophic keratopathy (NK), with corneal ulceration, scarring, and ultimately, blindness1. Having identified nerve-ensheathing Schwann cells (SC) in the corneal limbus, we hypothesize that SCs, via paracrine interaction with LSC, play a key role in corneal epithelial maintenance and healing.
In this study we wanted to 1) Define the role of SCs in corneal healing 2) Determine the paracrine interaction between the limbal SCs and LSC.
Methods: 1) Local corneal ablation of SCs was induced in a genetically modified mouse where the topical application of tamoxifen induced SCs apoptosis2. The corneal epithelium was then removed with an Amoils brush under anesthesia and fluorescein was used to assess healing over 4 days. 2) We performed single-cell RNA expression analysis of 10,000 cells derived from dissociated rat limbus with droplet-based high throughput 10x Genomics to identify ~3000 genes3. We used the data to predict possible ligand-receptor interactions between the limbal SCs and LSC.
Results: 1) Ablation of SCs impaired corneal wound healing in mouse cornea, suggesting the involvement of SC in innervation-dependent corneal epithelial recovery. 2) Genomic analysis suggested the presence of paracrine crosstalk between SCs and LSCs, and relevant downstream intracellular signaling events in LSCs. The latter included activation of Notch signaling and VEGF-mediated cell migration and inhibition of apoptosis4. Further expression analysis comparing the limbal region of healthy and wounded corneas indicated significant changes in the expression of jag1, Pdgfa, Tgfb1, and Ptn genes by SCs. All of these genes could potentially play a role in corneal recovery.
Conclusion: Our findings i) describe the presence of a high volume of SCs at the limbus, located in close spatial vicinity to LSCs, ii) demonstrate the importance of the limbal SCs for corneal wound healing, and iii) suggest the presence of paracrine SC-LSC interaction that may be responsible for the limbal nerve-mediated activation of LSCs during homeostasis or the epithelial wound healing after injury. These findings suggest new therapeutic targets for treating NK.


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