1434 Role of fibroblast DPP4 in wound healing, scarring and regeneration

Abstract

Wounding results in inflammation, synthesis and remodeling of granulation tissue with extracellular matrix deposition and scar-formation which might reduce function of affected areas representing a challenging medical problem. During development and even in the presence of inflammation skin repair is scarless until fibroblasts become lineage-committed and express DPP4. The exact functions of this molecule remain unknown. It is hypothesized that through its peptidase activity DPP4 is able to modulate the microenvironment around fibroblasts at specific time points during wound healing and repair and thus determine the fate and function of these cells and others. We performed in vivo experiments applying 1.5x1.5 cm full-thickness wounds on the back of mice and analyzed gene and protein expression on sorted fibroblasts and tissue sections. We can show that DPP4 is expressed and upregulated in early stages of wounding but then reduced at the moment Wnt-activity and fibrogenic differentiation occurs suggesting a regulatory role for DPP in the scar formation process but also for Wnt pathway which is crucial for tissue regeneration. Blocking DPP4 early upon wounding results in abolishment of “wound induced hair follicle neogenesis (WIHN)” and increased dermal thickness while lack of DPP4-activity at later stages results in increased WIHN, a hallmark of regenerative repair. Our data suggests a crucial role for DPP4 for scarring and WIHN and further investigations might help elucidate the molecular mechanisms involved in supporting the wound healing functions of dermal fibroblast and inducing their scar-forming activities, which might help identifying targets for improving skin-regeneration.