Single cell active force generation under dynamic loading - Part II: Active modelling insights.

In Part I of this two-part study a novel single cell AFM experimental investigation reveals a complex force-strain response of cells to cyclic loading. The biomechanisms underlying such complex behaviour cannot be fully understood without a detailed mechanistic analysis incorporating the key features of active stress generation and remodelling of the actin cytoskeleton. In order to simulate untreated contractile cells an active bio-chemo-mechanical model is developed, incorporating the key features of stress fibre (SF) remodelling and active tension generation. It is demonstrated that a fading memory SF contractility model accurately captures the transient response of cells to dynamic loading. Simulations reveal that high stretching forces during unloading half-cycles (probe retraction) occur due to tension actively generated by axially oriented SFs. On the other hand, hoop oriented SFs generate tension during loading half-cycles, providing a coherent explanation for the elevated compression resistance of contractile cells. Finally, it is also demonstrated that passive non-linear visco-hyperelastic material laws, traditionally used to simulate cell mechanical behaviour, are not appropriate for untreated contractile cells, and their use should be limited to the simulation of cells in which the active force generation machinery of the actin cytoskeleton has been chemically disrupted. In summary, our active modelling framework provides a coherent understanding of the biomechanisms underlying the complex patterns of experimentally observed single cell force generation presented in the first part of this study. STATEMENT OF SIGNIFICANCE: A novel computational investigation into the active and passive response of cells to dynamic loading is performed. An active formulation that considers key features of actin cytoskeleton active contractility and remodelling throughout the cytoplasm is implemented. Simulations provide new insights into the sub-cellular biomechanical response, providing a coherent explanation for the complex patterns of cell force uncovered experimentally in the first part of this study. Our computational models also reveal that passive non-linear visco-hyperelastic material laws, traditionally used to simulate cell mechanical behaviour, are not appropriate for untreated contractile cells, and their use should be limited to the simulation of cells in which the active force generation machinery of the actin cytoskeleton has been chemically disrupted.