Tensile force-induced cytoskeletal remodeling: Mechanics before chemistry

Abstract

Understanding cellular remodeling in response to mechanical stimuli is a critical step in elucidating mechanical activation of biochemical signaling pathways. Experimental evidence indicates that external stress-induced subcellular adaptation is accomplished through dynamic cytoskeletal reorganization. To study the interactions between subcellular structures involved in transducing mechanical signals, we combined experimental data and computational simulations to evaluate real-time mechanical adaptation of the actin cytoskeletal network. Actin cytoskeleton was imaged at the same time as an external tensile force was applied to live vascular smooth muscle cells using a fibronectin-functionalized atomic force microscope probe. Moreover, we performed computational simulations of active cytoskeletal networks under an external tensile force. The experimental data and simulation results suggest that mechanical structural adaptation occurs before chemical adaptation during filament bundle formation: actin filaments first align in the direction of the external force by initializing anisotropic filament orientations, then the chemical evolution of the network follows the anisotropic structures to further develop the bundle-like geometry. Our findings present an alternative two-step explanation for the formation of actin bundles due to mechanical stimulation and provide new insights into the mechanism of mechanotransduction.

Understanding cytoskeletal avalanches using mechanical stability analysis

“…Using MEDYAN, we performed simulations of small cytoskeletal networks consisting of 50 actin filaments in 1- hard-walled cubic boxes with varying concentrations of -actinin cross-linkers ( ) and of NMIIA myosin-motor minifilaments ( ) ( 13 , 20 , 31 – 33 ). We omit here other associated proteins, such as the branching agent Arp2/3, finding that our minimal system is sufficient to produce heavy-tailed distributions of event sizes, although it has recently been discovered that branching acts to enhance avalanche-like processes ( 34 ).…”

“…One can ask if by tuning the strength of this or other cytoquake-modulating factors, the network is more or less responsive to external perturbation. This perturbation could be introduced either mechanically, for example, through a simulated or real-force microscopy experiment, or chemically, through a variation of the chemical boundary conditions ( 33 ). Such studies should clarify whether large events in cytoskeletal dynamics serve a biologically useful purpose.…”

“…To computationally study cytoskeletal networks at high spatiotemporal resolution, we used the simulation platform MEDYAN ( 13 , 20 , 31 – 33 ). We provide an in-depth discussion of how MEDYAN works in SI Appendix , Description of MEDYAN Simulation Platform .…”

Mechanical programming of arterial smooth muscle cells in health and ageing

“…Upon mechanical loading, ASMCs reorganise their actin cytoskeleton via a two-step response. Seconds after a force is applied, actin filaments are stretched and align along the direction of the force (Li et al 2020 ). A few minutes later, actin filaments become stabilised through the ATP-dependent process of αSMA crosslinking.…”

Simulations of dynamically cross-linked actin networks: morphology, rheology, and hydrodynamic interactions

“…A recent study [87] also used microscopic Brownian dynamics simulations to show that the observed local maximum in the viscous modulus [47] corresponds to a maximum in CL binding and unbinding events, implying that maximum dissipation occurs when the CL unbinding timescale matches the timescale of the imposed deformation. There have also been a number of computational studies on the structure and contractile behavior of actomyosin networks, which show that a critical concentration of α -actinin cross-linkers can combine with myosin motors to form ordered bundles of actin filaments with varying polarity [69, 45].…”