Fibrosis is often untreatable and is characterized by aberrant tissue scarring from activated myofibroblasts. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues impact myofibroblast differentiation in 3D is poorly understood. Here we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure hallmark to the interstitial tissue regions where idiopathic pulmonary fibrosis (IPF) initiates. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was inversely correlated with hydrogel stiffness, but positively correlated with matrix fiber density. Employing a multi-step bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix-metalloprotease activity to be essential for 3D but not 2D myofibroblast differentiation. Given our observation that compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for studying fibrosis.

中文翻译：

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微工程3D肺间质模拟物突显了特发性肺纤维化中基质降解的关键作用

纤维化通常是无法治愈的，其特征是活化的成纤维细胞会产生异常的组织疤痕。尽管细胞外基质在疾病发展过程中变得越来越僵硬和纤维化，但这些物理线索如何影响3D中成肌纤维细胞的分化却知之甚少。在这里，我们描述了一种多组分水凝胶，可将3D纤维结构概括为特发性肺纤维化（IPF）起始的间质组织区域。与2D水凝胶的发现相反，3D中的成肌纤维细胞分化与水凝胶硬度成反比，但与基质纤维密度成正比。采用IPF患者转录组的多步生物信息学分析和体外药理学筛选，我们确定基质金属蛋白酶活性对于3D而非2D成肌纤维细胞的分化至关重要。鉴于我们的观察结果，即顺应性可降解3D矩阵可充分支持纤维发生，因此这些研究表明背离了2D硬度和成肌纤维细胞分化之间已建立的关系，并提供了研究纤维化的新3D模型。