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Accelerating Wound Closure with Metrnl in Normal and Diabetic Mouse Skin

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posted on 2023-08-28, 14:54 authored by Lingyu Song, Xuebing Chang, Laying Hu, Lu Liu, Guifang Wang, Yali Huang, Lifen Xu, Bangming Jin, Jianying Song, Lixin Hu, Tian Zhang, Yuanyuan Wang, Ying Xiao, Fan Zhang, Mingjun Shi, Lingling Liu, Qi Chen, Bing Guo, Yuxia Zhou

Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like, Metrnl) accelerates wound epithelialization and angiogenesis in mice. We observed a significant increase in Metrnl expression during physiological wound healing; however, its expression remained low during diabetic wound healing. 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. 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. Meanwhile, M2 macrophages secrete Metrnl to further stimulate angiogenesis. 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. In conclusion, our study suggests that Metrnl has a biological activity in accelerating wound closure through c-Kit-dependent angiogenesis and epithelialization.

Funding

This study was supported by National Natural Science Foundation of China (No. 82000741, 32160207, 82170743, 82060111). China Postdoctoral Science Foundation (2020M683374), Guizhou Provincial Science and Technology Projects (ZK [2021]402), and Universities Young Science and Technology Talent Growth Project in Guizhou Province (KY [2021]170). Excellent Young Talents Plan of Guizhou Medical University (2021105). Guizhou Provincial Natural Science Foundation (No [2021]4029 and [2022]4017).

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