Identifying the mechanism(s) of scarless corneal wound healing in Acomys cahirinus (The African Spiny mice) and Mus musculus - SUMMARY Rodents from the genus Acomys (Affrican Spiny mice) have recently emerged as a powerful model for regeneration, being capable of fully regenerating sections of skin without scarring including the development of new skin appendages. The regenerative capabilities of the Acomys species is not limited to the skin, with studies also demonstrating they can regenerate skeletal muscle tissue, cartilage, kidney, peripheral nerves and digits. Thus, the Acomys are a powerful animal model to understand the cellular and molecular mechanisms that promote regeneration with limited scarring in mammals. Aim 1a of this proposal will establish whether the Acomys cahirinus are capable of scarless corneal wound healing by comparing the regenerative capabilities of the cornea of A. cahirinus to the Mus musculus following alkali burn (AB). Aim 1b will then characterize and compare the mechanisms of wound healing between the A. cahirinus and M. musculus. This aim will establish for the first time whether A. cahirinus are capable of scarless corneal wound healing and identify the mechanism by which A. cahirinus are capable of regenerating a transparent cornea following AB. Our lab has been using the AB model on mice of diverse genetic backgrounds for well over a decade. Over the years, we have collated significant longitudinal data to show that when a group of wild-type mice on the same genetic background, such as C57BL/6J, are subjected to AB of equal severity, some mice are able to regenerate their corneas with limited to no scarring by day 14 (~18% of mice), while the others present corneal scarring (~82%). Curiously, our unpublished data show that the mice that present corneal scarring by day 14 present significant inflammatory cell infiltration and severe epithelial defect at day 1, while mice that are able to regenerate a transparent cornea by day 14 do not. Thus, excessive inflammatory infiltration within the first 24 hours following injury dictates whether the cornea will regenerate or suffer corneal scarring. Aim 2 of this proposal will characterize and compare the wound healing process between inbred C57BL/6J mice that are able to regenerate the cornea following AB to those that present corneal scarring, identifying for the first time key factors that direct corneal wound healing into wound resolution and regeneration instead of corneal scarring. Clinical Significance: Corneal scarring after trauma is a leading cause of vision loss in our society. To date, there are limited treatment options for preventing and treating corneal scarring, culminating in an urgent medical need for new therapeutics that can promote scarless wound healing. This proposal will identify key cellular and molecular mechanisms that regulate scarless wound healing establishing the groundwork for developing novel therapies for triggering scarless wound healing in the clinic.
