Adventitial fibroblasts (AFs) are major contributors to vascular remodeling and maladaptive cascades associated with arterial disease, where AFs both contribute to and respond to alterations in their surrounding matrix. The relationships between matrix modulus and human aortic AF (AoAF) function are investigated using poly(ethylene glycol)-based hydrogels designed with matrix metalloproteinase (MMP)-sensitive and integrin-binding peptides. Initial equilibrium shear storage moduli for the substrates examined are 0.33, 1.42, and 2.90 kPa; after 42 days of culture, all hydrogels exhibit similar storage moduli (0.3-0.7 kPa) regardless of initial modulus, with encapsulated AoAFs spreading and proliferating. In 10 and 7.5 wt% hydrogels, modulus decreases monotonically throughout culture; however, in 5 wt% hydrogels, modulus increases after an initial 7 days of culture, accompanied by an increase in myofibroblast transdifferentiation and expression of collagen I and III through day 28. Thereafter, significant reductions in both collagens occur, with increased MMP-9 and decreased tissue inhibitor of metalloproteinase-1/-2 production. Releasing cytoskeletal tension or inhibiting cellular protein secretion in 5 wt% hydrogels block the stiffening of the polymer matrix. Results indicate that encapsulated AoAFs initiate cell-mediated matrix remodeling and demonstrate the utility of dynamic 3D systems to elucidate the complex interactions between cell behavior and substrate properties.

中文翻译：

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人类外源成纤维细胞表型取决于底物刚度变化的进程。

后代成纤维细胞（AF）是与动脉疾病相关的血管重塑和适应不良的级联反应的主要贡献者，其中AF都对周围基质的改变做出贡献并做出反应。使用基于基质金属蛋白酶（MMP）敏感和整联蛋白结合肽设计的基于聚乙二醇的水凝胶，研究基质模量与人主动脉AF（AoAF）功能之间的关系。所检查基材的初始平衡剪切储能模量为0.33、1.42和2.90 kPa。培养42天后，无论初始模量如何，所有水凝胶均表现出相似的储能模量（0.3-0.7 kPa），并且包囊的AoAF扩散并增殖。在10和7.5 wt％的水凝胶中，模量在整个培养过程中单调降低；但是，在5 wt％的水凝胶中，在开始培养的第7天后，弹性模量增加，伴随着成纤维细胞转分化的增加以及在第28天时胶原I和III的表达增加。此后，两种胶原均显着减少，MMP-9增多而金属蛋白酶-1的组织抑制剂减少/ -2生产。在5 wt％的水凝胶中释放细胞骨架张力或抑制细胞蛋白质分泌会阻碍聚合物基质的硬化。结果表明，封装的AoAF可引发细胞介导的基质重塑，并证明了动态3D系统可阐明细胞行为与底物特性之间的复杂相互作用。MMP-9的增加和金属蛋白酶-1 / -2生成的组织抑制剂的减少均会导致两种胶原蛋白的显着减少。在5 wt％的水凝胶中释放细胞骨架张力或抑制细胞蛋白质分泌会阻碍聚合物基质的硬化。结果表明，封装的AoAF可引发细胞介导的基质重塑，并证明了动态3D系统可阐明细胞行为与底物特性之间的复杂相互作用。MMP-9的增加和金属蛋白酶-1 / -2生成的组织抑制剂的减少均会导致两种胶原蛋白的显着减少。在5 wt％的水凝胶中释放细胞骨架张力或抑制细胞蛋白质分泌会阻碍聚合物基质的硬化。结果表明，封装的AoAF可引发细胞介导的基质重塑，并证明了动态3D系统可阐明细胞行为与底物特性之间的复杂相互作用。