Combination therapy accelerates diabetic wound closure.
Combination therapy accelerates diabetic wound closure.
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DOI：
10.1371/journal.pone.0092667
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Warren SM
中科院分区：
文献类型：
--
作者：
Allen RJ Jr;Soares MA;Haberman ID;Szpalski C;Schachar J;Lin CD;Nguyen PD;Saadeh PB;Warren SM
不愈合的足部溃疡是发达国家糖尿病患者非创伤性截肢和住院的最常见原因。受损的伤口新血管形成延续了功能失调的组织修复和再生的循环。有证据表明，骨髓来源的祖细胞（PC）的动员缺陷是糖尿病新生血管受损的根本原因。目前，没有FDA批准的治疗方法来解决这一缺陷。在这里，我们报告了一种内源性PC策略，通过AMD 3100和PDGF-BB的联合治疗来改善糖尿病伤口新血管形成和闭合，AMD 3100通过竞争性结合细胞表面CXCR 4受体来动员骨髓来源的PC，PDGF-BB是一种已知可增强细胞生长、祖细胞迁移和血管生成的蛋白质。将受伤的小鼠分配到5个实验组中的1个（n = 8/组）：盐水处理的野生型、盐水处理的糖尿病、AMD 3100处理的糖尿病、PDGF-BB处理的糖尿病和AMD 3100/PDGF-BB处理的糖尿病。 分析每组的循环PC数量和伤口血管分布（n = 8/组）。 在存在AMD 3100的情况下评估细胞功能。使用经验证的II型糖尿病伤口愈合的临床前模型，我们表明，单独使用AMD 3100治疗（10 mg/kg;每天腹腔注射）可以挽救PC动员中的糖尿病特异性缺陷，但不能恢复正常的伤口新血管形成。通过进一步研究，我们证明了AMD 3100治疗的糖尿病PC中的获得性运输缺陷，可以通过在伤口环境中补充PDGF-BB（2 μg;局部）来挽救。最后，我们确定联合治疗可恢复糖尿病伤口新血管形成，并使伤口闭合时间加快40%。AMD 3100和PDGF-BB联合治疗可协同改善BM PC动员和运输，从而显着改善糖尿病伤口闭合和新血管形成。使用FDA批准的疗法改善糖尿病伤口愈合的这种内源性、基于细胞的策略的成功本质上是可转化的。
Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis. Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 μg; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%. Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.
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3.6
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