The lung extracellular matrix (ECM) maintains the structural integrity of the tissue and regulates the phenotype and functions of resident fibroblasts. Lung-metastatic breast cancer alters these cell-ECM interactions, promoting fibroblast activation. There is a need for bio-instructive ECM models that match the ECM composition and biomechanics of the lung to study these cell-matrix interactions in vitro. Here, a synthetic, bioactive hydrogel is synthesized that mimics the native lung modulus and includes a representative distribution of the most abundant ECM peptide motifs responsible for integrin-binding and matrix metalloproteinase (MMP)-mediated degradation in the lung, which enables quiescent culture of human lung fibroblasts (HLFs). Stimulation with transforming growth factor β1 (TGF-β1), metastatic breast cancer conditioned media (CM), or tenascin-C-derived integrin-binding peptide activated hydrogel-encapsulated HLFs demonstrates multiple environmental methods to activate HLFs in a lung ECM-mimicking hydrogel. This lung hydrogel platform is a tunable, synthetic approach to studying the independent and combinatorial effects of ECM in regulating fibroblast quiescence and activation.

中文翻译：

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Tenascin-C 激活 3D 合成肺细胞外基质模拟物中的肺成纤维细胞

肺细胞外基质（ECM）维持组织的结构完整性并调节常驻成纤维细胞的表型和功能。肺转移性乳腺癌改变了这些细胞-ECM 相互作用，促进成纤维细胞活化。需要与肺的 ECM 成分和生物力学相匹配的生物指导 ECM 模型来在体外研究这些细胞-基质相互作用。在这里，合成了一种合成的生物活性水凝胶，模拟天然肺模量，并包含最丰富的 ECM 肽基序的代表性分布，这些基序负责整合素结合和基质金属蛋白酶 (MMP) 介导的肺内降解，从而能够静态培养人肺成纤维细胞（HLF）。用转化生长因子 β1 (TGF-β1)、转移性乳腺癌条件培养基 (CM) 或生腱蛋白-C 衍生的整联蛋白结合肽激活的水凝胶封装的 HLF 进行刺激，证明了在模拟肺 ECM 的水凝胶中激活 HLF 的多种环境方法。该肺水凝胶平台是一种可调节的合成方法，用于研究 ECM 在调节成纤维细胞静止和激活方面的独立和组合效应。