Neuronal-epithelial cell alignment: A determinant of health and disease status of the cornea.

How sensory neurons and epithelial cells interact with one another, and whether this association can be considered an indicator of health or disease is yet to be elucidated. Herein, we used the cornea, Confetti mice, a novel image segmentation algorithm for intraepithelial corneal nerves which was compared to and validated against several other analytical platforms, and three mouse models to delineate this paradigm. For aging, eyes were collected from 2 to 52 week-old normal C57BL/6 mice (n ≥ 4/time-point). For wound-healing and limbal stem cell deficiency, 7 week-old mice received a limbal-sparing or limbal-to-limbal epithelial debridement to their right cornea, respectively. Eyes were collected 2-16 weeks post-injury (n=4/group/time-point), corneas procured, immunolabelled with βIII-tubulin, flat-mounted, imaged by scanning confocal microscopy and analyzed for nerve and epithelial-specific parameters. Our data indicate that nerve features are dynamic during aging and their curvilinear arrangement align with corneal epithelial migratory tracks. Moderate corneal injury prompted axonal regeneration and recovery of nerve fiber features. Limbal stem cell deficient corneas displayed abnormal nerve morphology, and fibers no longer aligned with corneal epithelial migratory tracks. Mechanistically, we discovered that nerve pattern restoration relies on the number and distribution of stromal-epithelial nerve penetration sites. Microstructural changes to innervation may explain corneal complications related to aging and/or disease and facilitate development of new assays for diagnosis and/or classification of ocular and systemic diseases.

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