Moreover, the keratinocyte- and macrophage-produced cytokine Metrnl drives post-injury angiogenesis and re-epithelialization through activation of AKT phosphorylation (S473) in a KIT receptor tyrosine kinase (c-Kit)-dependent manner. Meanwhile, M2 macrophages secrete Metrnl to further stimulate angiogenesis. Mechanistically, keratinocytes secrete quantities of Metrnl to promote angiogenesis, increase endothelial cell proliferation, migration and tube formation, and enhance macrophage polarization to the M2 type. Functionally, the recombinant protein Metrnl significantly accelerated wound closure in normal and diabetic mice models including db/db, high-fat diet/streptozotocin (HFD/STZ), and STZ mice. We observed a significant increase in Metrnl expression during physiological wound healing however, its expression remained low during diabetic wound healing. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like, Metrnl) accelerates wound epithelialization and angiogenesis in mice. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes.

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