A major challenge in the management of patients suffering from diabetes is the risk of developing nonhealing foot ulcers. Most in vitro methods to screen drugs for wound healing therapies rely on conventional 2D cell cultures that do not closely mimic the complexity of the diabetic wound environment. In addition, while three-dimensional (3D) skin tissue models of human skin exist, they have not previously been adapted to incorporate patient-derived macrophages to model inflammation from these wounds. In this study, we present a 3D human skin equivalent (HSE) model incorporating blood-derived monocytes and primary fibroblasts isolated from patients with diabetic foot ulcers (DFUs). We demonstrate that the monocytes differentiate into macrophages when incorporated into HSEs and secrete a cytokine profile indicative of the proinflammatory M1 phenotype seen in DFUs. We also show how the interaction between fibroblasts and macrophages in the HSE can guide macrophage polarization. Our findings take us a step closer to creating a human, 3D skin-like tissue model that can be applied to evaluate the response of candidate compounds needed for potential new foot ulcer therapies in a more complex tissue environment that contributes to diabetic wounds.

中文翻译：

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一种评估糖尿病巨噬细胞功能的新型三维皮肤病模型

糖尿病患者管理中的一个主要挑战是发生不愈合足部溃疡的风险。大多数体外筛选用于伤口愈合疗法的药物的方法依赖于传统的 2D 细胞培养物，这些培养物不能密切模仿糖尿病伤口环境的复杂性。此外，虽然存在人体皮肤的三维 (3D) 皮肤组织模型，但它们以前并未被调整以结合患者来源的巨噬细胞来模拟这些伤口的炎症。在这项研究中，我们提出了一个 3D 人体皮肤等效 (HSE) 模型，该模型结合了从糖尿病足溃疡 (DFU) 患者中分离出的血液来源的单核细胞和原代成纤维细胞。我们证明单核细胞在掺入 HSE 时分化为巨噬细胞，并分泌一种细胞因子谱，表明 DFU 中可见的促炎 M1 表型。我们还展示了 HSE 中成纤维细胞和巨噬细胞之间的相互作用如何引导巨噬细胞极化。