Cellular poroelasticity

What is poroelasticity?

One of the most striking features of eukaryotic cells is their capacity to change shape in response to environmental or intrinsic cues thanks to their actomyosin cytoskeleton. In studies of cellular morphogenesis, the cytoplasm is generally viewed as an innocuous backdrop enabling diffusion of signalling proteins. This view misses a major point: the time-dependent mechanical properties (or rheology) of cells are mainly determined by their cytoplasm because it forms the largest part of the cell by volume. During gross morphogenetic changes such as cell rounding, cytokinesis, cell spreading, or cell movement, the cytoskeleton provides the force for morphogenesis but the maximal rate at which shape change can occur is dictated by the rate at which the cytoplasm can be deformed. Whereas the static mechanical properties of cells (elasticity) have been studied in depth, the time-dependent mechanical properties of cells have received significantly less attention. The majority of the work to date utilises a viscoelastic description of cells that assumes the cytoplasm is a single phase homogenous material. Though these models fit experimental data well, they fail to relate the measured rheological properties to structural or biological parameters within the cell. An alternative description has been proposed based on the framework of poroelasticity, in which the cytoplasm is biphasic consisting of a porous elastic solid meshwork (cytoskeleton, organelles, macromolecules) bathed in an interstitial fluid (cytosol). In this framework, the viscoelastic properties of the cell are a manifestation of the time needed for redistribution of intracellular fluids in response to applied mechanical stresses and the response of the cell to force application depends on a single experimental parameter: the poroelastic diffusion constant , with larger poroelastic diffusion constants corresponding to more rapid stress relaxations.

Past work

We have shown that water redistribution plays a significant role in cellular responses to mechanical stresses at short timescales and that the effect of osmotic and cytoskeletal perturbations on cellular rheology can be understood in the framework of poroelasticity. Force-relaxation induced by fast localised indentation by AFM contained two regimes: at short time-scales, relaxation was poroelastic; while at longer time-scales, it exhibited a power law behaviour [1].

Currently in the lab

Such poroelastic properties have profound consequences for our understanding of the physical basis of cell migration and mechanotransduction because they imply the existence of intracellular pressure gradients and presence of intracellular fluid flows during these processes. However, a direct proof that cytoplasmic poroelastic properties play an important role over lengthscales and timescales relevant to cell physiology is lacking. In recent work using a combination of electrophysiological methods and super-resolution microscopy techniques, we have shown experimentally that cells can sustain transient and prolonged pressure gradients across their cytoplasm in response to extrinsic and intrinsic mechanical stresses. Overall our data suggest that intracellular pressure gradients may play a much greater role than currently appreciated in mechanotransduction, cell polarisation, and cell migration.

Relevant publications:

[1] Moeendarbary, E., Valon, L., Fritzsche, M., Harris, A.R., Moulding, D.A., Thrasher, A.J., Stride, E., Mahadevan, L. and Charras, G.T., 2013. The cytoplasm of living cells behaves as a poroelastic material. Nature materials12(3), pp.253-261.

[2] Record, J., Malinova, D., Zenner, H.L., Plagnol, V., Nowak, K., Syed, F., Bouma, G., Curtis, J., Gilmour, K., Cale, C., Hackett, S., Charras G, Moulding D, Nejentsev S, Thrasher AJ, Burns SO. 2015. Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1. Blood126(13), pp.1527-1535.

Collaborators on this project:

Adrian Thrasher (Institute of Child Health, UCL, London, UK)

L Mahadevan (Harvard University, USA)

Funding on this project:

Wellcome Trust grant