Caliari Steven R, Vega Sebastián L, Kwon Michelle, Soulas Elizabeth M, Burdick Jason A
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Biomaterials. 2016 Oct;103:314-323. doi: 10.1016/j.biomaterials.2016.06.061. Epub 2016 Jun 29.
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.
深入了解细胞如何解读微环境信号对于设计更好的生物材料疗法至关重要。YAP/TAZ是机械敏感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（如硬度和可降解性）与培养维度之间复杂相互作用的调控。我们使用具有可控硬度（通过交联密度）和可降解性（通过交联对蛋白水解的敏感性）的共价交联降冰片烯功能化透明质酸（HA）水凝胶，发现人间充质干细胞（MSCs）在较硬水凝胶上培养时表现出更大的铺展和YAP/TAZ核定位；然而，当MSCs封装在可降解水凝胶中时观察到相反的趋势。当使用硬度匹配但可降解性降低的水凝胶时，能够铺展的细胞中YAP/TAZ核转位更大，这通过YAP/TAZ和肌动蛋白聚合的药理学抑制得到证实。总之，这些数据表明YAP/TAZ信号传导对水凝胶硬度和可降解性有反应，但结果取决于细胞 - 生物材料相互作用的维度。
