Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing
Hua Qu1, Tian Miao1,2, Yuren Wang1
1Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, Department of Endocrinology, Second Affiliated Hospital of Army Medical University, Chongqing, China.
Abstract:
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.
Insights
Dedicator of cytokinesis 5 (Dock5) is crucial for skin wound healing by regulating keratinocyte functions and extracellular matrix deposition. Restoring Dock5 improves healing in diabetic models, offering a therapeutic target for diabetic foot ulcers.
Area of Science:
- Cell Biology
- Dermatology
- Biochemistry
Background:
- Cutaneous wound healing is vital for tissue homeostasis.
- Dysfunctional healing, particularly in diabetic foot ulcers, poses a significant health burden.
- The molecular mechanisms underlying effective skin repair remain incompletely understood.
Purpose of the Study:
- To investigate the role of dedicator of cytokinesis 5 (Dock5) in keratinocyte function and skin wound healing.
- To elucidate the molecular pathways influenced by Dock5 during wound repair.
- To assess the therapeutic potential of Dock5 in the context of diabetes-impaired wound healing.
Main Methods:
- Investigated Dock5 expression during wound repair in mice.
- Examined Dock5's effects on keratinocyte adhesion, migration, and proliferation in vitro.
- Utilized genetic ablation and overexpression models in mice.
- Analyzed extracellular matrix (ECM) deposition and related signaling pathways (Laminin-332/integrin).
- Assessed Dock5 expression in human and animal models of diabetes.
Main Results:
- Dock5 is upregulated during the proliferative phase of wound healing and essential for keratinocyte functions.
- Dock5 facilitates ECM deposition by ubiquitinating ZEB1, activating laminin-332/integrin signaling.
- Genetic deletion of Dock5 impairs reepithelialization and granulation tissue formation.
- Reduced Dock5 expression correlates with impaired healing in diabetic conditions.
- Restoring Dock5 in diabetic mice significantly enhances reepithelialization, collagen deposition, and ECM production.
Conclusions:
- Dock5 plays a pivotal role in regulating keratinocyte functions critical for skin wound healing.
- Dock5-mediated activation of laminin-332/integrin signaling is key to its pro-healing effects.
- Dock5 deficiency exacerbates impaired wound healing in diabetes.
- Targeting Dock5 represents a promising therapeutic strategy for treating diabetic wound healing complications.
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