The mechanics of the extracellular matrix (ECM) determine cell activity and fate through mechanoresponsive proteins including Yes-associated protein 1 (YAP). Rigidity and viscous relaxation have emerged as the main mechanical properties of the ECM steering cell behavior. However, how cells integrate coexisting ECM rigidity and viscosity cues remains poorly understood, particularly in the high-stiffness regime. Here, we have exploited engineered stiff viscoelastic protein hydrogels to show that, contrary to current models of cell-ECM interaction, substrate viscous energy dissipation attenuates mechanosensing even when cells are exposed to higher effective rigidity. This unexpected behavior is however readily captured by a pull-and-hold model of molecular clutch–based cell mechanosensing, which also recapitulates opposite cellular response at low rigidities. Consistent with predictions of the pull-and-hold model, we find that myosin inhibition can boost mechanosensing on cells cultured on dissipative matrices. Together, our work provides general mechanistic understanding on how cells respond to the viscoelastic properties of the ECM.

中文翻译：

---

细胞对细胞外基质粘性能量耗散的反应超过了高刚性传感


细胞外基质 （ECM） 的机制通过机械反应蛋白（包括 Yes 相关蛋白 1 （YAP））决定细胞活性和命运。刚度和粘性松弛已成为 ECM 转向单元行为的主要机械性能。然而，细胞如何整合共存的 ECM 刚性和粘度线索仍然知之甚少，尤其是在高刚度状态下。在这里，我们利用工程刚性粘弹性蛋白质水凝胶表明，与当前细胞-ECM 相互作用的模型相反，即使细胞暴露于更高的有效刚度，基质粘性能量耗散也会衰减机械感应。然而，这种意想不到的行为很容易被基于分子离合器的细胞机械感应的拉握模型捕获，该模型还在低刚性下概括了相反的细胞反应。与拉握模型的预测一致，我们发现肌球蛋白抑制可以增强耗散基质上培养的细胞的机械感应。总之，我们的工作提供了关于细胞如何响应 ECM 粘弹性的一般机制理解。