A multiscale whole-cell theory for mechanosensitive migration on viscoelastic substrates

Area of Science:

• Cell Biology
• Biophysics
• Mechanobiology

Background:

• Extracellular matrix (ECM) mechanics, including stiffness and viscosity, critically influence mesenchymal cell behavior and migration patterns.
• Mesenchymal cells exhibit complex motility responses, including durotaxis, anti-durotaxis, and adurotaxis, which are sensitive to ECM properties.

Purpose of the Study:

• To develop a multiscale chemomechanical theory that elucidates the mechanisms governing the switch between different mesenchymal cell migration regimes.
• To investigate how intracellular signaling pathways, specifically Rho GTPase proteins, interact with ECM mechanical cues to direct cell movement.

Main Methods:

• Developed a multiscale whole-cell theory coupling subcellular focal adhesion dynamics, cytoskeletal mechanics, and Rho GTPase signaling pathways.
• Simulated mesenchymal cell migration on substrates with varying uniform stiffness and in the presence of stiffness gradients.
• Analyzed the influence of substrate viscosity on cell migration efficiency and directionality.

Main Results:

• The model quantitatively reproduces experimental cell migration speeds as a function of substrate stiffness and explains viscosity effects.
• Simulated cells exhibit durotaxis, anti-durotaxis, or adurotaxis in response to stiffness gradients, depending on substrate stiffness and viscosity.
• Demonstrated that Rho GTPase gradients can override mechanical cues, reversing migration direction.

Conclusions:

• The interplay between intracellular signaling (Rho GTPase) and cell-ECM mechanical interactions governs complex mechanosensing and diverse cell migration behaviors.
• The developed theory provides a mechanistic explanation for opposing durotactic responses observed in mesenchymal cells.
• This framework advances the understanding of single-cell mechanosensing and cell migration regulation.