| Summary: | Cells sense and generate both internal and external forces. They resist and transmit these forces to the cell interior or to other cells. Moreover a variety of cellular responses are excited and influenced by transducing mechanical stimulations into chemical signals that lead to changes in cellular behaviour. The cytoplasm represents the largest part of the cell by volume and hence its rheology sets the maximum rate at which any cellular shape change can occur. To date, the cytoplasm has generally been modelled as a single-phase viscoelastic material; however, recent experimental evidence suggests that its rheology can be described more effectively using a poroelastic formulation in which the cytoplasm is considered to be a biphasic system constituted of a porous elastic solid meshwork (cytoskeleton, organelles, macromolecules) bathing in an interstitial fluid (cytosol). In this framework, a single parameter, the poroelastic diffusion constant p D , sets cellular rheology scaling as ~ 2 / p D Ex m with E the elastic modulus, x the hydraulic pore size, and m the cytosolic viscosity. Though this poroelastic view of the cell is a conceptually attractive model, direct supporting evidence has been lacking. In this work, such evidence is presented and the concept of a poroelastic cell is validated to explain cellular rheology at physiologically relevant time-scales. In this work, the functional form of stress relaxation in response to rapid application of a localised force by atomic force microscopy microindentation is examined in detail and it is shown that at short time-scales cellular relaxations are poroelastic. Then, p D is measured in cells by fitting experimental stress relaxation curves to the theoretical model. VI Next, using indentation tests in conjunction with osmotic perturbations, the validity of the predicted scaling of p D with pore size is qualitatively verified. Using chemical and genetic perturbations, it is shown that cytoplasmic rheology depends strongly on the integrity of the actin cytoskeleton but not on microtubules or intermediate filaments. Finally, comparison of scaling of viscoelastic and poroelastic models suggests that shorttime scale viscoelasticity might be due to water redistribution within the cytoplasm and a simple scaling relating cytoplasmic viscosity to cellular microstructure is provided.
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