Wound healing is impaired under diabetes, and the proliferative phase of healing, mainly the charge of epidermal keratinocytes, is essential for tissue repair. Failure to maintain this process contributes to the dysfunction of tissue homeostasis and global burden; however, the factors that mediate this process are not fully understood. Here, we identified dedicator of cytokinesis 5 (Dock5) as a critical regulator of cutaneous wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte migration and proliferation and influences the functions of angiogenesis and extracellular matrix (ECM) deposition by binding with integrin α3 (Itgα3). Genetic ablation of Dock5 in mice leads to attenuated re-epithelialization and granulation tissue formation, while Itgα3 overexpression improves the repressive effects on skin repair seen in Dock5 KO mice. Moreover, in patients and animal models of diabetes, Dock5 expression at the skin edge is reduced, further suggesting a direct correlation between its abundance and healing capability. Rescuing Dock5 expression in diabetic mice causes a significant improvement in re-epithelialization, angiogenesis, collagen deposit, ECM production and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.
Y. Zheng: None. H. Qu: None.
Army Medical University (2017R013, 2019XQYYYJ003-2)