This study used novel, force-limited nanoscale tension gauges to investigate how force and substrate stiffness guide cellular decision-making during initial cell attachment and spreading on deformable substrates. The well-established dependence of cell traction and spreading on substrate stiffness has been attributed to levels of force exerted on molecular components in focal contacts. The molecular tension gauges used in this study enabled direct estimates of threshold, pico Newton forces that instructed decision-making at different stages of cell attachment, spreading, and adhesion maturation. Results show that the force thresholds controlling adhesion and spreading transitions depend on substrate stiffness. Reported findings agree qualitatively with a proposed model that attributes rigidity-dependent differences in cell spreading to stiffness-dependent rates of competing biochemical processes. Moreover, estimated magnitudes of force thresholds governing transitions in cell attachment and spreading, based on these in situ measurements, were in remarkable agreement with prior less direct measurements.
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