Fibrosis, characterized by aberrant tissue scarring from activated myofibroblasts, is often untreatable. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues affect myofibroblast differentiation in 3D is poorly understood. Here, we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure of 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 fibers. Using a multistep bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix metalloproteinase 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 and identifying antifibrotic therapeutics.

以活化的肌成纤维细胞形成异常组织瘢痕为特征的纤维化通常是无法治疗的。尽管在疾病进展过程中细胞外基质变得越来越僵硬和纤维化，但这些物理线索如何影响 3D 中的肌成纤维细胞分化却知之甚少。在这里，我们描述了一种多组分水凝胶，它概括了特发性肺纤维化 (IPF) 引发的间质组织区域的 3D 纤维结构。与 2D 水凝胶上的发现相反，3D 中的肌成纤维细胞分化与水凝胶刚度呈负相关，但与基质纤维呈正相关。使用 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 而不是 2D 肌成纤维细胞分化至关重要。