Chemo-Mechanical Factors That Limit Cellular Force Generation

Abstract

Cellular traction forces that are dependent on actin-myosin activity are necessary for numerous developmental and physiological processes. As traction force emerges as a promising cancer biomarker there is a growing need to understand force generation in response to chemical and mechanical cues. Our goal is to present a unified modeling framework that integrates actin-myosin activity, substrate stiffness, integrin bond type, and adhesion complex dynamics to explain how force develops under specific conditions. Our simulation results show that substrate stiffness and number of myosin motors contribute to the maximum actin-myosin forces that can be generated but do not solely control the force transmitted by the cells to the surface, i.e., the traction force. The kinetics of the bonds between the cell and the substrate plays an equally important role. Overall, we find that while the cell can generate large actin-myosin forces in individual stress fibers (> 300 pN), the maximum force transmitted to the surface per cell-substrate attachment only reaches a fraction of these values (approx. 50 pN). Traction stress, the sum of forces transferred by all cell-substrate attachments in a unit area, is biphasic or sigmoidal with increasing substrate stiffness depending on the number of active myosin motors generating forces. Finally, we conclude that adhesions < 1 μm2 generate widely variable traction forces and that impulse, the magnitude and duration of a force generating event, is a key limiting factor in traction stress.

Predicting phenotype to mechanotype relationships in cells based on intra-cellular signaling network

“…Individually high ECM promotes ppMLC only in cell type II, no change in cell type I and increases focal adhesion in both cell types. In between the low and high states of ECM (0.1 -1.0), it is noticed that ECM modifies FA portion of the CEAMs in a biphasic manner (Supplementary Figure S2) along the lines of prior literature 55,77,78 . On the other hand, RTK signaling increases ppMLC and FA, but the change is more dramatic in cell type II.…”

“…The first submodule in the cytoskeleton network is MT signaling (module 3), which is integrated into network with mass-action kinetic differential equations. 54 and the kγ and kε parameters are extracted from Hidalgo-Vasquez study 55 . In catch-slip bond dynamics, as tension increases, bond lifetime has a biphasic trajectory, with lifetime increasing first and subsequently decreasing with applied tension.…”

“…Estimating the states of these nodes in response to ongoing biochemical signaling and using them as inputs to mechanical models helps connect cellular biochemistry to cellular mechanics. For now, this has been achieved simplistically by connecting intra-cellular tension generation in the current network, T, to the levels of f-actin, myosin phosphorylation and ECM signaling in an empirical manner based on existing mechanical models 55 .However, in the future a more direct integration between BoHyM and the mechanical models is envisioned. The model also allows backward integrations of mechanical signals from the environment, neighboring cells etc.…”

Predicting phenotype to mechanotype relationships in cells based on intracellular signaling network

“…The other parameters, kδ and kε are disassembly rates in Equations {10} and {11} , both are by the function of ECM and Actin-myosin Tension ( X i ). Catch-slip dynamics model is used 54 and the kγ and kε parameters are extracted from Hidalgo-Vasquez study 55 . In catch-slip bond dynamics, as tension increases, bond lifetime has a biphasic trajectory, with lifetime increasing first and subsequently decreasing with applied tension.…”

Identification of CD44 as a key mediator of cell traction force generation in hyaluronic acid-rich extracellular matrices

“…Cell surface adhesion receptors and cytoskeletal molecules are two critical components for traction force generation [20][21][22]. Adhesion receptor β1-integrins mechanically link the actin filaments within the cell with the collagen fibers within the ECM, and are responsible for the traction force transmission from the cell to the ECM [23][24][25][26][27].…”