YAP/TAZ is a master regulator of mechanotransduction whose functions rely on translocation from the cytoplasm to the nucleus in response to diverse physical cues. Substrate stiffness, substrate dimensionality, and cell shape are all input signals for YAP/TAZ, and through this pathway, regulate critical cellular functions and tissue homeostasis. Yet, the relative contributions of each biophysical signal and the mechanisms by which they synergistically regulate YAP/TAZ in realistic tissue microenvironments that provide multiplexed input signals remain unclear. For example, in simple two-dimensional culture, YAP/TAZ nuclear localization correlates strongly with substrate stiffness, while in three-dimensional (3D) environments, YAP/TAZ translocation can increase with stiffness, decrease with stiffness, or remain unchanged. Here, we develop a spatial model of YAP/TAZ translocation to enable quantitative analysis of the relationships between substrate stiffness, substrate dimensionality, and cell shape. Our model couples cytosolic stiffness to nuclear mechanics to replicate existing experimental trends, and extends beyond current data to predict that increasing substrate activation area through changes in culture dimensionality, while conserving cell volume, forces distinct shape changes that result in nonlinear effect on YAP/TAZ nuclear localization. Moreover, differences in substrate activation area versus total membrane area can account for counterintuitive trends in YAP/TAZ nuclear localization in 3D culture. Based on this multiscale investigation of the different system features of YAP/TAZ nuclear translocation, we predict that how a cell reads its environment is a complex information transfer function of multiple mechanical and biochemical factors. These predictions reveal a few design principles of cellular and tissue engineering for YAP/TAZ mechanotransduction.

YAP/TAZ 是机械转导的主要调节器，其功能依赖于从细胞质到细胞核的易位，以响应不同的物理信号。底物刚度、底物维度和细胞形状都是 YAP/TAZ 的输入信号，并通过该途径调节关键的细胞功能和组织稳态。然而，每个生物物理信号的相对贡献以及它们在提供多路输入信号的现实组织微环境中协同调节 YAP/TAZ 的机制仍不清楚。例如，在简单的二维培养中，YAP/TAZ 核定位与底物刚度密切相关，而在三维 (3D) 环境中，YAP/TAZ 易位可以随刚度增加、随刚度减小或保持不变。这里，我们开发了 YAP/TAZ 易位的空间模型，以实现对底物刚度、底物维数和细胞形状之间关系的定量分析。我们的模型将细胞质刚度与核力学相结合以复制现有的实验趋势，并超越当前数据预测通过培养维度的变化增加底物活化面积，同时保持细胞体积，迫使不同的形状变化，导致对 YAP/TAZ 的非线性影响核定位。此外，底物活化面积与总膜面积的差异可以解释 3D 培养中 YAP/TAZ 核定位的违反直觉趋势。基于对 YAP/TAZ 核易位不同系统特征的多尺度研究，我们预测细胞如何读取其环境是多种机械和生化因素的复杂信息传递函数。这些预测揭示了 YAP/TAZ 机械转导的细胞和组织工程的一些设计原则。