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Published on: August 21, 2021
CXXC5 function blockade promotes diabetic wound healing through stimulating fibroblast and vascular endothelial cell
Yutong Chen1, Xiaofeng Ding2, Zhouji Ma3,4
1Department of Burns and Plastic Surgery, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. 985881572@qq.com.
Background:
Extracellular matrix (ECM) and angiogenesis are critical controls of wound regeneration, and their dysfunction delays diabetes recovery. CXXC5 belongs to the CXXC protein family that can regulate the function of human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs); However, awareness of its functional role remains limited.
Methods:
Mice were divided into control (CON), diabetic (DM), diabetic + KY19382 (DM + KY19382), and diabetic + vehicle (DM + Vehicle) groups. HDFs and HUVECs were stimulated under different CXXC5 conditions and mice were treated with KY19382, followed by the application of assays including Western blotting (WB), immunofluorescence (IF) and quantitative reverse transcription-PCR (qRT-PCR) to assess wound healing and molecular signaling.
Results:
Mice in DM had fewer blood vessels, a slower wound healing rate, and more disrupted collagen than CON. Application of KY19382 improved these conditions, which promoted fibroblast activation and vascularization in high glucose environments and DM. Mechanistically, blocking CXXC5 promotes Wnt/β-catenin-mediated stabilization by reducing the binding of the deterrent factor CTBP1 to β-catenin, which induces dermal fibroblast activation and facilitates HUVECs tube formation and migration via VEGFA/VEGFR2 and NFκB signaling pathways. KY19382 promotes HUVECs activation by blocking CTBP1 transcription to activate the NFκB signaling pathway, thus wound re-vascularization.
Conclusion:
CXXC5 is an essential regulatory factor of wound healing and a prospective therapeutic target for treating chronic wound damage in diabetes.
Insights
Blocking CXXC5 with KY19382 enhances wound healing in diabetic mice by promoting fibroblast activation and vascularization. This study identifies CXXC5 as a key regulator in chronic wound repair.
Area of Science:
- Cell Biology
- Molecular Biology
- Regenerative Medicine
Background:
- Extracellular matrix (ECM) and angiogenesis are crucial for wound regeneration, but their dysfunction impairs healing in diabetes.
- CXXC5, a member of the CXXC protein family, influences human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs), yet its precise role in wound healing is not well-defined.
Purpose of the Study:
- To investigate the role of CXXC5 in diabetic wound healing.
- To evaluate the therapeutic potential of targeting CXXC5 using KY19382 in a diabetic wound model.
Main Methods:
- Diabetic and control mice were treated with KY19382 or vehicle.
- In vitro studies involved stimulating HDFs and HUVECs under varying CXXC5 conditions.
- Assays included Western blotting, immunofluorescence, and qRT-PCR to analyze molecular signaling and wound healing parameters.
Main Results:
- Diabetic mice exhibited impaired wound healing, reduced vascularization, and collagen disruption compared to controls.
- KY19382 treatment improved wound healing by enhancing fibroblast activation and vascularization in high glucose and diabetic conditions.
- Mechanistically, blocking CXXC5 stabilized Wnt/β-catenin signaling, promoted HUVEC tube formation and migration via VEGFA/VEGFR2 and NFκB pathways, and enhanced HUVEC activation by blocking CTBP1 transcription.
Conclusions:
- CXXC5 is a critical regulator of wound healing processes.
- Targeting CXXC5 with KY19382 shows promise as a therapeutic strategy for managing chronic diabetic wounds.
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