Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds
Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds
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DOI：
10.1089/ten.tec.2014.0414
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发表时间：
2015-05-01
影响因子：
3
通讯作者：
Garlick, Jonathan A.
中科院分区：
文献类型：
--
作者：
Maione, Anna G.;Brudno, Yevgeny;Garlick, Jonathan A.
糖尿病足溃疡（DFU）是糖尿病的一种主要的、使人衰弱的并发症。不幸的是，许多DFU对现有的治疗是难治的，并且经常导致截肢。由于缺乏预测性的体外方法来研究受损愈合的潜在机制，更有效的治疗方法的开发受到阻碍。为了解决现实的伤口愈合模型的需要，我们建立了患者来源的成纤维细胞DFU和现场匹配的控制，并使用它们来构建慢性伤口愈合的三维（3D）模型。将DFU衍生的成纤维细胞并入这些模型中准确地概括了慢性溃疡的以下关键方面：减少血管生成的刺激、增加角质形成细胞增殖、减少上皮再形成和受损的细胞外基质沉积。除了反映DFU的临床属性外，在这套模型中证明的DFU成纤维细胞的伤口愈合潜力与小鼠体内伤口闭合相关。因此，报告的3D DFU模型组提供了一个生物学相关性更高的平台，用于阐明慢性伤口发病机制的细胞-细胞和细胞-基质相关机制，并可改善体外发现转化为有效的临床应用。
Diabetic foot ulcers (DFU) are a major, debilitating complication of diabetes mellitus. Unfortunately, many DFUs are refractory to existing treatments and frequently lead to amputation. The development of more effective therapies has been hampered by the lack of predictive in vitro methods to investigate the mechanisms underlying impaired healing. To address this need for realistic wound-healing models, we established patient-derived fibroblasts from DFUs and site-matched controls and used them to construct three-dimensional (3D) models of chronic wound healing. Incorporation of DFU-derived fibroblasts into these models accurately recapitulated the following key aspects of chronic ulcers: reduced stimulation of angiogenesis, increased keratinocyte proliferation, decreased re-epithelialization, and impaired extracellular matrix deposition. In addition to reflecting clinical attributes of DFUs, the wound-healing potential of DFU fibroblasts demonstrated in this suite of models correlated with in vivo wound closure in mice. Thus, the reported panel of 3D DFU models provides a more biologically relevant platform for elucidating the cell-cell and cell-matrix-related mechanisms responsible for chronic wound pathogenesis and may improve translation of in vitro findings into efficacious clinical applications.