MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310058, China.
Biomaterials. 2018 Oct;180:193-205. doi: 10.1016/j.biomaterials.2018.07.022. Epub 2018 Jul 17.
Cell migration plays an important role in many physiological and biological processes, which is influenced by both physicochemical properties of surrounding matrix and signal gradient generated by neighboring/remote cells. Here we aim to develop a co-culture system of immune cells and smooth muscle cells (SMCs) based on the combination of Transwell and cell-responsive hydrogels. This model can be used to study the cell invasion into hydrogels in dynamic physiological conditions, with better mimicking of the in vivo microenvironment. Methacrylic anhydride-modified hyaluronic acid (MA-HA) macromolecules were crosslinked by matrix metalloproteinases (MMPs) sensitive peptides (MMP SP) to fabricate a cell-degradable hydrogel mimicking dynamic extracellular matrix (ECM). The migration of SMCs into the MMP-sensitive hydrogel was investigated under the existence of U937 cells, a type of macrophage-like cells. The invasion distance of SMCs in the MMP-sensitive hydrogels was much longer than that in the MMP-insensitive ones both in vitro and in vivo. The impact of hydrogel degradability and inductive signal gradient generated by U937 cells on cell invasion was compared, revealing that the degradability plays a major role in regulating cell invasion into the 3D hydrogels. Further mechanism investigation revealed that the expressions of cell migration-related genes and proteins were significantly up-regulated in the MMP-sensitive hydrogels compared to those in the MMP-insensitive hydrogels.
细胞迁移在许多生理和生物过程中起着重要作用，它受到周围基质的物理化学性质和邻近/远程细胞产生的信号梯度的影响。在这里，我们旨在开发一种基于 Transwell 和细胞响应水凝胶的免疫细胞和平滑肌细胞（SMCs）共培养系统。该模型可用于在动态生理条件下研究细胞侵入水凝胶的情况，更好地模拟体内微环境。用基质金属蛋白酶（MMPs）敏感肽（MMP SP）交联甲基丙烯酰化透明质酸（MA-HA）大分子，制备一种细胞可降解的水凝胶，模拟动态细胞外基质（ECM）。在 U937 细胞（一种巨噬细胞样细胞）存在的情况下，研究了 SMC 向 MMP 敏感水凝胶中的迁移。在 MMP 敏感水凝胶中，SMC 的侵入距离比在 MMP 不敏感水凝胶中要长得多，无论是在体外还是体内。比较了水凝胶降解性和 U937 细胞产生的诱导信号梯度对细胞侵入的影响，结果表明降解性在调节细胞侵入 3D 水凝胶中起着主要作用。进一步的机制研究表明，与 MMP 不敏感水凝胶相比，MMP 敏感水凝胶中细胞迁移相关基因和蛋白的表达显著上调。
