DKK1 Targeting in Corneal Schwann Cells Rescues Axonal Regeneration and Mechanosensory Function After Corneal Injury

Stromal nerves regulate the sensory functions of the cornea, which can be disrupted by surgical, traumatic, or chemical injuries. Corneal Schwann cells (cSCs) ensheath axons to provide trophic support, but their role in axonal regeneration is still unexplored. We utilized the proteolipid protein 1-enhanced green fluorescent protein (Plp1-eGFP) reporter mice to investigate cSCs in two models of corneal nerve injury: the corneal micropocket injury (CMI) model, which causes focal stromal axonal severance, and acute exposure to nitrogen mustard (NM), which results in blunt damage across the entire cornea and limbal tissue. After CMI, the cSC network declined rapidly over 7 days post-injury (dpi) but recovered to levels of uninjured controls by 14 dpi with sprouting at both the injury and collateral areas. Axons remained significantly lower than cSCs, compromising mechanosensory functions. The NM injury led to a sustained cSC and axonal deficit with persistent mechanosensory loss through 14 dpi. Previously, we identified Dickkopf-related protein 1 (DKK1) as a novel candidate gene expressed in cSCs. In this study, we developed a micellar formulation RM4404 incorporating a small-molecule DKK1 inhibitor for topical application and tested the therapeutic potential of this drug in both injury models. Application of RM4404 during the cSC regenerative phase (7-14 dpi) enhanced cSC repair and significantly improved axonal regeneration with restoration of mechanosensory function in both injury paradigms. These findings identify a promising DKK1-targeted therapy that promotes cSC repair, enhances corneal nerve regeneration, and restores sensory function in models of corneal injury.