MC1R reduces scarring and rescues stalled healing in a preclinical chronic wound model

Abstract

Cutaneous wound healing typically results in scarring; however, chronic wounds (CWs) represent a global and escalating health burden causing substantial morbidity and mortality. Estimated to cost Medicare up to $96.8 billion pa and with a profound paucity of effective therapeutics, novel interventions to improve healing are urgently needed. In this study, we assess the impact of manipulating the melanocortin 1 receptor (MC1R) on acute wound healing using a selective agonist, BMS-470539 (MC1R-Ag). MC1R agonism resulted in accelerated wound closure and reepithelialisation in wildtype but not MC1Re/e mice, which harbour a non-functional receptor. MC1R-Ag improved wound perfusion and lymphatic drainage by promoting angiogenesis and lymphangiogenesis, reducing local oxidative stress and inflammation with a knock-on effect of reduced scarring. To assess whether manipulating MC1R would be of benefit in pathological healing, we developed a novel murine model of chronic cutaneous wounds. By combining advanced age and locally elevated oxidative stress, factors shown to be present in most human CWs regardless of their category, resultant wounds expand 5-fold into the surrounding tissue, produce exudate and generate slough. Histological comparisons to human CWs demonstrate robust recapitulation of the hallmarks of human disease, including hyperproliferative epidermis, fibrinous exudate and vasculitis. Crucially, our model facilitates the in vivo study of candidate therapies to rescue derailed healing responses. We have identified that abrogation of MC1R signalling, using MC1Re/e mice, exacerbates CWs with enhanced exudate and NETosis. In contrast, topical administration of an MC1R agonist following ulcer debridement rescues the healing response, highlighting MC1R agonism as a candidate therapeutic approach for human CWs. We anticipate that our unique model will become a valuable tool to elucidate mechanisms of ulcer development and persistence.