Schwann Cells Are Required For Efficient Corneal Wound Healing
kaveh mirmoeini, MD, MSc1, Kiana Tajdaran, MD, MSc1, konstantin Feinberg, PhD1, Jennifer Zhang, MD,PhD2, Tessa Gordon, PhD1, Asim Ali, MD3, Gregory Borschel, MD1.
1University of Toronto, toronto, ON, Canada, 2Hospital for the sick children, toronto, ON, Canada, 3The hospital for sick children, toronto, ON, Canada.
Background: Corneal nerves play a crucial role in maintaining corneal health, which includesregulation of activity of limbal stem cell (LSC). Their loss leads to neurotrophic keratopathy (NK),with corneal ulceration, scarring, and ultimately, blindness1. Having identified nerve-ensheathingSchwann cells (SC) in the corneal limbus, we hypothesize that SCs, via paracrine interaction withLSC, 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 theparacrine interaction between the limbal SCs and LSC.Methods: 1) Local corneal ablation of SCs was induced in a genetically modified mouse wherethe topical application of tamoxifen induced SCs apoptosis2. The corneal epithelium was thenremoved with an Amoils brush under anesthesia and fluorescein was used to assess healing over4 days. 2) We performed single-cell RNA expression analysis of 10,000 cells derived fromdissociated rat limbus with droplet-based high throughput 10x Genomics to identify ~3000genes3. We used the data to predict possible ligand-receptor interactions between the limbal SCsand LSC.Results: 1) Ablation of SCs impaired corneal wound healing in mouse cornea, suggesting theinvolvement of SC in innervation-dependent corneal epithelial recovery. 2) Genomic analysissuggested the presence of paracrine crosstalk between SCs and LSCs, and relevant downstreamintracellular signaling events in LSCs. The latter included activation of Notch signaling and VEGF-mediated cell migration and inhibition of apoptosis4. Further expression analysis comparing thelimbal region of healthy and wounded corneas indicated significant changes in the expression ofjag1, Pdgfa, Tgfb1, and Ptn genes by SCs. All of these genes could potentially play a role in cornealrecovery.Conclusion: Our findings i) describe the presence of a high volume of SCs at the limbus, locatedin close spatial vicinity to LSCs, ii) demonstrate the importance of the limbal SCs for cornealwound healing, and iii) suggest the presence of paracrine SC-LSC interaction that may beresponsible for the limbal nerve-mediated activation of LSCs during homeostasis or the epithelialwound healing after injury. These findings suggest new therapeutic targets for treating NK.1.Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathy. Published online 2018.2.Johnston APW, Naska S, Jones K, Jinno H, Kaplan DR, Miller FD. Sox2-mediated regulation ofadult neural crest precursors and skin repair. Stem Cell Rep. 2013;1(1):38-45.doi:10.1016/j.stemcr.2013.04.0043.Yuzwa SA, Borrett MJ, Innes BT, et al. Developmental Emergence of Adult Neural Stem Cells asRevealed by Single-Cell Transcriptional Profiling. Cell Rep. 2017;21(13):3970-3986.doi:10.1016/j.celrep.2017.12.0174.Lindsell CE, Shawber CJ, Boulter J, Weinmaster G. Jagged: A mammalian ligand that activatesnotch1. Cell. 1995;80(6):909-917. doi:10.1016/0092-8674(95)90294-5
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