Decoupling cellular response to topography and stiffness in three dimensions
Decoupling cellular response to topography and stiffness in three dimensions
复制标题
解耦细胞对三维地形和刚度的反应
DOI：
10.1101/232066
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
K. Tanner
中科院分区：
文献类型：
--
作者：
C. Paul;Alex M. Hruska;J. Staunton;Hannah A. Burr;Jiyun Kim;N. Jiang;K. Tanner
体内组织微环境的生物物理学方面包括细胞外基质（ECM）的微尺度机械特性、纤维排列、结构或形貌以及存在的ECM配体库，所有这些都提供了驱动细胞应答的线索。细胞-ECM相互作用是正常组织稳态和恶性肿瘤的重要调节剂。因此，了解细胞外信号和它们引起的细胞反应是开发治疗策略的基础。用于3D细胞培养和组织工程的各种体外平台已被用于研究细胞对微环境的反应。然而，在三维组织模拟物中以受控方式再现体内存在的组织结构的多样性使用天然来源的ECM水凝胶是具有挑战性的。在这里，我们使用自下而上的方法来构建纤维状结构到3D无定形水凝胶中，使用与人类ECM蛋白功能化的磁性胶体颗粒的自组装。使用与器官特异性病理状态相关的人ECM蛋白。我们确定，虽然含有对齐的纤维或随机分布的胶体颗粒的水凝胶的散装组织力学是相似的，对齐的水凝胶在对齐的纤维附近的微观力学性能表现出空间异质性。然后，我们使用这个平台与定义的弹性模量的2D基板相结合，以将拓扑结构的作用与正常细胞和肿瘤细胞的微尺度组织力学分离。我们确定，地形线索占主导地位的人类和正常细胞的细胞反应，其响应独立于微尺度力学和ECM组成的3D水凝胶。这些数据表明，地形单独可以驱动基本的细胞反应，如极化和迁移的正常和转化细胞。
Biophysical aspects of in vivo tissue microenvironments include microscale mechanical properties, fibrillar alignment, architecture or topography of the extracellular matrix (ECM), and the repertoire of ECM ligands present, all of which provide cues to drive cellular response. Cell-ECM interactions are important regulators of both normal tissue homeostasis and malignancy. Thus, understanding both extracellular cues and the cellular responses they elicit is fundamental to developing therapeutic strategies. Various in vitro platforms for 3D cell culture and tissue engineering have been used to study cellular response to the microenvironment. However, recapitulating the diversity of tissue architectures present in vivo in a controlled manner in three-dimensional tissue mimetics is challenging using naturally derived ECM hydrogels. Here, we use a bottom-up approach to build fibrillar architecture into 3D amorphous hydrogels using self-assembly of magnetic colloidal particles functionalized with human ECM proteins. Human ECM proteins associated with organ-specific pathological states were used. We determined that, while the bulk tissue mechanics of hydrogels containing either aligned fibers or randomly distributed colloidal particles were similar, aligned hydrogels exhibited spatial heterogeneities in microscale mechanical properties near aligned fibers. We then used this platform in combination with 2D substrates of defined elastic modulus to decouple the role of topography from microscale tissue mechanics for normal and tumor cells. We determined that topographical cues dominate cellular response for human and normal cells, which responded independently of microscale mechanics and ECM composition in 3D hydrogels. These data suggest that topography alone can drive fundamental cellular responses such as polarization and migration for both normal and transformed cells.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
影响因子：
6
作者：
Conklin, Matthew W.;Eickhoff, Jens C.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.
影响因子：
3.4
作者：
Riching, Kristin M.;Cox, Benjamin L.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.
影响因子：
32.4
作者：
Bajenoff, Marc;Egen, Jackson G.;Germain, Ronald N.
通讯作者：
Germain, Ronald N.
影响因子：
7.3
作者：
Wolf K;Alexander S;Schacht V;Coussens LM;von Andrian UH;van Rheenen J;Deryugina E;Friedl P
通讯作者：
Friedl P