Journal
DIABETES
Volume 70, Issue 5, Pages 1170-1184Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db20-1008
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Funding
- National Science Fund for Distinguished Young Scholars [81925007]
- National Natural Science Foundation of China [82000769, 82070881, 82070836, 81700714, 81721001, 81970752]
- Talent Project of the Army Medical University [2017R013, 2019R047, 2019XQYYYJ003-2]
- Macau Young Scholars Program [AM201918]
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Dock5 plays a pivotal role in skin wound healing by regulating keratinocyte functions during the proliferative phase, impacting various aspects of the healing process. This study suggests a potential therapeutic target for improving wound healing impairment in diabetic individuals.
Cutaneous wound healing is a fundamental biologic and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify the pivotal role of dedicator of cytokinesis 5 (Dock5) in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration, and proliferation and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated reepithelialization and granulation tissue formation, and Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in reepithelialization, collagen deposition, ECM production, and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.
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