Timing Mechanotransduction: Mechanically Dynamic Biomaterials Reveal the Temporal Hierarchy of YAP/TAZ Control Nodes

Area of Science:

• Cell biology
• Biophysics
• Biomaterials

Background:

• Mechanotransduction, the process by which cells sense and respond to mechanical cues, is crucial for cell behavior.
• The precise temporal dynamics and hierarchical nature of mechanotransduction remain incompletely understood.

Purpose of the Study:

• To investigate the spatiotemporal dynamics of mechanotransduction in response to dynamic substrate stiffness changes.
• To establish a temporal framework for mechanotransduction events on physiologically relevant timescales.

Main Methods:

• Development of dynamically softening polyacrylamide hydrogels for in situ stiffness modulation.
• Time-resolved analyses of cell responses, including YAP/TAZ activity, cytoskeletal organization, and focal adhesion dynamics.
• Investigating the roles of SUN2 and cellular contractility in mechanosensing.

Main Results:

• A biphasic cellular response to extracellular softening was observed.
• Early softening led to abrupt YAP/TAZ inactivation and collapse of the LINC complex-nucleo-cytoskeletal continuum, while peripheral adhesions remodeled.
• Later softening at lower thresholds induced nuclear flattening, cell rounding, and peripheral adhesion collapse; reactivation of YAP/TAZ required cyclic strain.

Conclusions:

• Established a spatiotemporal framework for dynamic mechanotransduction, highlighting distinct temporal events.
• Identified key nodes and timing-based constraints that differentiate initiating events from downstream adaptations in mechanotransduction.
• Demonstrated directionally asymmetric mechanotransduction with abrupt inactivation and strain-dependent reactivation.