The co-evolution of adhesion and F-actin gives rise to hierarchical cellular force generation

Abstract

Cells --- the basic units of life --- dynamically adhere to their micro-environment, build their F-actin cytoskeleton, and apply molecular-motor generated contractile forces to it in a remarkably broad range of biological processes and physiological functions, in both health and disease. Yet, how these processes are orchestrated over multiple spatiotemporal scales is not fully understood. Using several experimental approaches and a theoretical framework, we show that adhesion assembly, on-adhesion F-actin accumulation and the contractile force itself all follow the same time evolution over tens of minutes, the cellular force timescale, at well-defined adhesion sites. We also show that the F-actin distribution away from the adhesion site features a multiplicative space-time decomposition. Finally, we show that F-actin retrograde flow --- central in the so-called molecular motor-clutch models --- is markedly faster than force generation rates, that it does not slow down over maturing adhesions and that its density drops at adhesion sites. These findings suggest a hierarchical, multi- scale force generation process that is controlled by slow adhesion recruitment, which is accompanied by rapid, bursty linear actin polymerization. The linear F-actin slowly accumulates with adhesion recruitment to form an extended near-adhesion F-actin network to which molecular motors attach and apply elastic-like contraction.