Strategy to activate ephrin-Eph signaling pathways and develop a novel therapeutic approach to regenerative wound repair in veterinary medicine 2259503

Abstract Introduction Intact skin is an essential part of innate immunity. In horses, full-thickness distal limb wounds are common and the limited amount of surrounding soft tissue creates forces that prevent primary closure. Repair is also complicated by granulation tissue that forms continually in the absence of epithelial cover, eventually elevating above intact skin. Its irregular surface blocks repair by disrupting keratinocyte proliferation and migration. In other words, excessive granulation tissue blocks re-epithelialization, the main mechanism for distal limb wound closure. While agents that specifically promote re-epithelialization are clinically unavailable, research indicates ephrin-Eph signaling pathways provide targets for strategies that stimulate keratinocyte proliferation and migration. As example, we newly reported topical treatment with a commercially available rEFNA3 protein reversed progestin-mediated vaginal epithelial thinning in mice. Methods We posited ephrin-Eph signaling pathways that stimulate keratinocyte proliferation are an unexplored but effective strategy for accelerating re-epithelialization of full-thickness distal limb horse wounds. To test this hypothesis, we first used rationale design to newly create a potent EFNA3 mimetic agonist peptide (EFNA3-MAP). We then enrolled 10 horses and compared repair in full-thickness distal limb wounds administered EFNA3-MAP in hydrogel vs. hydrogel alone. Results Compared to controls, EFNA3-MAP treatment significantly accelerated keratinocyte proliferation and migration (as measured by gross examination and histology) and this rapid re-epithelialization prevented formation of excessive granulation tissue. Conclusion Our data suggest ephrin-Eph pathways are an important target for agents designed to stimulate regenerative healing. As re-epithelialization is the main mechanism for cutaneous wound closure in horses and humans, our results have the potential to create strategies that enhance cutaneous wound management in equine and human medicine. Funding Source State of Ohio Accelerator Award Topic Categories Veterinary and Comparative Immunology (VET)