Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments.
Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments.
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DOI：
10.1016/j.biomaterials.2016.06.061
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发表时间：
2016-10
期刊：
影响因子：
14
通讯作者：
Burdick JA
中科院分区：
文献类型：
--
作者：
Caliari SR;Vega SL;Kwon M;Soulas EM;Burdick JA
改善对细胞如何解释微环境信号的基本理解对于设计更好的生物材料疗法是不可或缺的。雅普/TAZ是机械敏感性信号传导的关键介质;然而，尚不清楚它们如何受到微环境因素（例如，硬度和可降解性）和培养维度。使用具有受控刚度（通过交联密度）和可降解性（通过交联对蛋白水解的敏感性）的共价交联的石墨烯官能化的透明质酸（HA）水凝胶，我们发现当在更硬的水凝胶上培养时，人间充质干细胞（MSC）显示增加的扩散和雅普/TAZ核定位;然而，当MSC被封装在可降解水凝胶内时，观察到相反的趋势。当使用降解性降低的刚度匹配的水凝胶时，雅普/TAZ核转位在能够扩散的细胞中更大，这通过雅普/TAZ和肌动蛋白聚合的药理学抑制来证实。总之，这些数据表明，雅普/TAZ信号是响应于水凝胶的刚度和降解性，但结果是依赖于细胞-生物材料相互作用的维度。
Improved fundamental understanding of how cells interpret microenvironmental signals is integral to designing better biomaterial therapies. YAP/TAZ are key mediators of mechanosensitive signaling; however, it is not clear how they are regulated by the complex interplay of microenvironmental factors (e.g., stiffness and degradability) and culture dimensionality. Using covalently crosslinked norbornene-functionalized hyaluronic acid (HA) hydrogels with controlled stiffness (via crosslink density) and degradability (via susceptibility of crosslinks to proteolysis), we found that human mesenchymal stem cells (MSCs) displayed increased spreading and YAP/TAZ nuclear localization when cultured atop stiffer hydrogels; however, the opposite trend was observed when MSCs were encapsulated within degradable hydrogels. When stiffness-matched hydrogels of reduced degradability were used, YAP/TAZ nuclear translocation was greater in cells that were able to spread, which was confirmed through pharmacological inhibition of YAP/TAZ and actin polymerization. Together, these data illustrate that YAP/TAZ signaling is responsive to hydrogel stiffness and degradability, but the outcome is dependent on the dimensionality of cell-biomaterial interactions.