Physical biology of cell-substrate interactions under cyclic stretch

Area of Science:

• Cellular mechanics
• Biophysics
• Computational biology

Background:

• Mechanosensitive focal adhesions (FAs) are crucial for cell-substrate interactions, regulating cellular functions through integrin-ligand binding and stress fiber (SF) dynamics.
• Integrins within FAs link extracellular matrix ligands to intracellular SFs, enabling load transfer and cellular traction generation.

Purpose of the Study:

• To develop and utilize a multi-scale, stochastic finite element model to investigate the dynamic interplay between cellular components and substrate properties.
• To quantify the effects of substrate stiffness, ligand density, and cyclic stretch on fibroblast mechanosensing and force generation.

Main Methods:

• Developed a one-dimensional, multi-scale, stochastic finite element model of a fibroblast on a substrate.
• Incorporated calcium signaling, SF remodeling, and FA dynamics, linking stochastic integrin clustering to a continuum SF contractility model.
• Quantified cellular responses including tractions, integrin recruitment, and cytosolic calcium levels under varying substrate and mechanical conditions.

Main Results:

• Cellular tractions and integrin recruitment varied spatially, with maximums at lamellar regions and reduced forces at the cell center.
• Optimal substrate stiffness for maximum cell traction shifted towards stiffer substrates with increased ligand density.
• Cyclic stretch modulated cytosolic calcium, integrin concentrations, and tractions, particularly on compliant substrates, and could induce cell deadhesion on stiff substrates.

Conclusions:

• Chemomechanical coupling is essential for understanding cell-substrate mechanosensing.
• Substrate stiffness, ligand density, and mechanical stretch significantly influence cellular force generation and adhesion dynamics.
• The developed model provides insights into how physical and chemical cues regulate cell behavior and mechanical responses.