Context-Dependent Roles of Mouse Corneal Epithelial Cell-Derived Exosomes in Diabetic Corneal Wound Healing

Delayed corneal wound healing and sensory neuropathy are hallmarks of diabetic keratopathy, yet the role of corneal epithelial cell (CEC)-derived exosomes in these processes remains unclear. This study characterized exosomes secreted by the mouse corneal epithelial progenitor cell line TKE2 at either quiescent state or scratch-wounded. The isolated extrasellar vesicles wer characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blotting. Exosomal cargo was analyzed by LC-MS/MS proteomics. The roles of exosome and selected proteins were assessed for effects on wounded healing of normoglycemic and streptozotocin-induced diabetic C57BL/6J mice. The isolated vesicles exhibited canonical exosomal features and were readily taken up by CEC at 1 dpw and trigeminal sensory neurons at 3 dpw. Exosomes derived from healing, but not quiescent, cultures accelerated delayed epithelial wound closure in diabetic corneas, while having little effect on normoglycemic corneas. HTRA1, enriched in healing exosomes, contributed to epithelial wound healing in normal corneas, as its inhibition attenuated wound closure in normoglycemic but not diabetic mice. In contrast, treating healing exosomes with a STAT3 inhibitor, which permanently blocks its activity without altering protein content, partially reduced exosome-mediated wound healing in diabetic corneas. Collectively, these findings support context-dependent effects of CEC-derived exosomes in corneal wound repair and suggest that exosomal components may contribute to the regulation of diabetic corneal wound healing.