Soluble Receptor for Advanced Glycation End Products Improves Stromal Cell-Derived Factor-1 Activity in Model Diabetic Environments
Soluble Receptor for Advanced Glycation End Products Improves Stromal Cell-Derived Factor-1 Activity in Model Diabetic Environments
复制标题
DOI：
10.1089/wound.2015.0674
复制
发表时间：
2016-12-01
影响因子：
4.9
通讯作者：
Berthiaume, Francois
中科院分区：
文献类型：
--
作者：
Olekson, Melissa Przyborowski;Faulknor, Renea A.;Berthiaume, Francois
目的：在糖尿病中，高血糖症导致晚期糖基化终产物（AGEs）的积累，AGEs通过结合AGEs受体（AGEs）触发活性氧（ROS）的产生。由于外源性生长因子在促进慢性伤口愈合方面收效甚微，我们研究了高血糖诱导的AGEs是否会干扰细胞对细胞外信号的反应。我们使用了基质细胞衍生因子-1（SDF-1），一种血管生成趋化因子，也被认为可以促进皮肤伤口中干细胞的募集。方法：将表达SDF-1受体CXCR-4的人白血病-60（HL-60）细胞和小鼠外周血单核细胞（PBMC）在补充有25 mM d-葡萄糖的培养基中孵育24小时。用可溶性β-内酰胺酶（Soluble β-内酰胺酶，sNAR）阻断β-内酰胺酶的激活。在细胞迁移和ROS测定中测量对SDF-1的响应。糖尿病小鼠切除伤口模型测量了SDF-1脂质体和脂质体在体内的活性。结果如下：高血糖导致AGEs的显著积累，SDF-1介导的迁移减少，基线ROS水平升高;它抑制了通常由SDF-1触发的ROS峰值。sodium降低ROS基线，并恢复SDF-1介导的尖峰和细胞迁移。局部应用的sodium单独促进愈合，并增强外源性SDF-1对糖尿病小鼠伤口的作用。创新：虽然有兴趣使用生长因子来改善伤口愈合，但这种策略在糖尿病伤口中基本无效。我们发现，sodium可以恢复信号，从而增强外源性应用的生长因子的影响。结论：在高血糖环境中，用sodium阻断sodium可以恢复SDF-1介导的细胞反应，并可能增强SDF-1在体内应用的有效性。
Objective: In diabetes, hyperglycemia causes the accumulation of advanced glycation end products (AGEs) that trigger reactive oxygen species (ROS) generation through binding the receptor for AGEs (RAGE). Because exogenous growth factors have had little success in enhancing chronic wound healing, we investigated whether hyperglycemia-induced AGEs interfere with cellular responses to extracellular signals. We used stromal cell-derived factor-1 (SDF-1), an angiogenic chemokine also known to promote stem cell recruitment in skin wounds. Approach: Human leukemia-60 (HL-60) cells and mouse peripheral blood mononuclear cells (PBMCs), which express the SDF-1 receptor CXCR-4, were incubated for 24h in medium supplemented with 25mM d-glucose. Soluble RAGE (sRAGE) was used to block RAGE activation. Response to SDF-1 was measured in cellular migration and ROS assays. A diabetic murine excisional wound model measured SDF-1 liposome and sRAGE activity in vivo. Results: Hyperglycemia led to significant accumulation of AGEs, decreased SDF-1-directed migration, and elevated baseline ROS levels; it suppressed the ROS spike normally triggered by SDF-1. sRAGE decreased the ROS baseline and restored both the SDF-1-mediated spike and cell migration. Topically applied sRAGE alone promoted healing and enhanced the effect of exogenous SDF-1 on diabetic murine wounds. Innovation: While there is interest in using growth factors to improve wound healing, this strategy is largely ineffective in diabetic wounds. We show that sRAGE may restore signaling, thus potentiating the effect of exogenously applied growth factors. Conclusion: Blocking RAGE with sRAGE restores SDF-1-mediated cellular responses in hyperglycemic environments and may potentiate the effectiveness of SDF-1 applied in vivo.