Cells have the ability to sense and actively respond to their mechanical environment. However, the bio-mechanisms underlying such behaviour are not fully understood. Our group takes a combined experimental and computational approach to investigate the active response of cells to external and environmental mechanical stimuli. Our aim is to improve understanding of stress-fibre (SF) evolution and force generation, factors driving gene expression and cell differentiation, and macro-scale tissue remodelling.
Our combined experimental/computational approach has explored several key aspects of cell behaviour, including the contractile response of cells spread on micro-posts (McGarry 2009, Ronan 2013, Ronan 2014), compression resistance of cells (McGarry 2009, Ronan 2012, Weafer 2013), shear resistance of cells (Ofek 2010, Dowling 2012), focal adhesion development and cell detachment (McGarry 2007, Dowling 2014), cell-cell junctions (Ronan 2015), cell dependence on substrate elasticity (Ronan 2014), and the active response to Micropipette Aspiration (Weafer 2012, Reynolds 2014).
We have examined the dynamic loading of cells, where it was found the active contractile forces dominate the cellular mechanical response (Weafer 2015). A fading memory SF contractility model accurately captures the transient response of cells under such loading conditions (Reynolds 2015). More recently, cell spreading has been investigated through consideration of the system free energy (McEvoy 2017), where it has been shown cells tend to assume a minimum free energy spread state.
Our active modelling framework provides a coherent understanding of the bio-mechanisms underlying the complex patterns of experimentally observed cellular force generation.
E McEvoy, SS Shishvan, VS Deshpande, JP McGarry, Thermodynamic modelling of the statistics of cell spreading on ligand coated elastic substrates, Biophysical Journal. doi:10.1016/j.bpj.2018.11.007
E McEvoy, VS Deshpande, JP McGarry, Free Energy Analysis of Cell Spreading. Journal Of The Mechanical Behavior Of Biomedical Materials. 74:283-295
Reynolds, N. H., McGarry, J. P. Single cell active force generation under dynamic loading – Part II: Active modelling insights. Acta Biomaterialia, 27:251-263, 2015
Weafer, P. P., Reynolds, N. H., Jarvis, S. P., McGarry, J. P. Single cell active force generation under dynamic loading – Part I: AFM Experiments. Acta Biomaterialia, 27:236-250, 2015.
W Ronan, RM McMeeking, CS Chen, JP McGarry, VS Deshpande. Cooperative contractility: The role of stress fibres in the regulation of cell-cell junctions. Journal of Biomechanics. 48(3), 520–528, 2015.
N. H. Reynolds, W. Ronan, E. P. Dowling, P. Owens, R. M. McMeeking, J. P. McGarry. On the Role of the Actin Cytoskeleton and Nucleus in the Biomechanical Response of Spread Cells. Biomaterials, 35 (13), 4015-4025, 2014.
Dowling E., McGarry JP. Influence of Spreading and Contractility on Cell Detachment. Annals of Biomedical Engineering. 42 (5), 1037-1048, 2014.
William Ronan, Vikram S. Deshpande, Robert M. McMeeking, J. Patrick McGarry. Cellular contractility and substrate elasticity: a numerical investigation of the actin cytoskeleton and cell adhesion. Biomechanics and Modeling in Mechanobiology. 13 (2), 417-435, 2014.
William Ronan, Vikram S. Deshpande, Robert M. McMeeking, J. Patrick McGarry. Simulation of the mechanical response of cells on micropost substrates. Journal of Biomechanical Engineering. 135 (10), 101012, 2013.
EP Dowling, W Ronan, P McGarry. Computational investigation of in situ chondrocyte deformation and actin cytoskeleton remodelling under physiological loading. Acta Biomaterialia. 9 (4), 5943-5955, 2013.
P Weafer, W Ronan, S Jarvis, P McGarry. Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression. Bulletin of Mathematical Biology. 75:1284-1303, 2013. DOI 10.1007/s11538-013-9812-y
William Ronan, Vikram S. Deshpande, Robert M. McMeeking, J. Patrick McGarry, Numerical investigation of the active role of the actin cytoskeleton in the compression resistance of cells, Journal of the Mechanical Behaviour of Biomedical Materials, 14, 143-157 2012.
Dowling, E.P., Ronan, W., Ofek,G., Deshpande, V.S., McMeeking, R.M., Athanasiou, K.A., McGarry, J.P., The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: A computational and experimental investigation. J. R. Soc. Interface, 9 (77), 3469-3479, 2012.
P. P. Weafer, J. P. McGarry, M. H. van Es, J. I. Kilpatrick, W. Ronan, D. R. Nolan, S. P. Jarvis. Stability enhancement of an atomic force microscope for long-term force measurement including cantilever modification for whole cell deformation. Review of Scientific Instruments. 83(9), 2012. doi.org/10.1063/1.4752023
McGarry, J.P., Characterization of Cell Mechanical Properties by Computational Modeling of Parallel Plate Compression. Annals of Biomedical Engineering, 37(11):2317-2325, 2009.
McGarry, J.P, J. Fu, M. Yang, C. Chen, R. McMeeking, A. Evans, V. Deshpande, Simulation of the contractile response of cells on an array of micro-posts. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 367(1902): p. 3477, 2009
Ofek, G., E. Dowling, R. Raphael, J.P. McGarry, K. Athanasiou, Biomechanics of single chondrocytes under direct shear. Biomechanics and Modeling in Mechanobiology, 9(2):153-162, 2009
McGarry, J.,P. McHugh, P.E., Modelling of in vitro chondrocyte detachment. Journal of the Mechanics and Physics of Solids, 56(4): p. 1554-1565, 2008
McGarry, J.P., O’Donnell, B.P., McHugh, P.E., McMeeking, R.M. Computational Examination of the Effect of Material Inhomogeneity on the Necking of Stent Struts Under Tensile Loading, Journal of Applied Mechanics,74 , 978-989, 2007.
Flaherty, B., McGarry, J.P., Mc Hugh, P.E., Mathematical Models of Cell Motility, Cell Biochemistry and Biophysics, 49(1): 14-18, 2007.
McGarry, J.P., Murphy, B.P. and McHugh, P.E., Computational mechanics modelling of cell-substrate contact during cyclic substrate deformation, Journal of the Mechanics and Physics of Solids, 53 (12): 2597-2637, 2005.
McGarry, J.P., Murphy, B.P. and McHugh, P.E., Prediction of changes in cell-substrate contact under cyclic substrate deformation using cohesive zone modelling, Mechanics of Biological Tissue, 1(1),177-187,2004.
Key Paper Overviews:
On the role of the actin cytoskeleton and nucleus in the biomechanical response of spread cells
|An experimental and computational investigation of the biomechanical response of the actin cytoskeleton and nucleus in spread cells during micropipette aspiration. We demonstrate that an active computational framework that incorporates stress fibre remodelling and contractility must be used in order to accurately simulate experimental results, including: aspiration length as a function of time for a range of applied aspiration pressures (500 Pa in figure); stress fibre distribution (Π) observed in immuno-fluorescent images of cells 5 minutes post application of aspiration pressure, and; complete deformation of the nucleus into the micropipette during aspiration. Furthermore, a detailed experimental-computational investigation of the nucleus mechanical behaviour is conducted. It is demonstrated that the nucleus is highly deformable in cyto, reaching strain levels in excess of 100%. Link to paper|
Cooperative contractility: The role of stress fibres in the regulation of cell-cell junctions
|Computational simulatio ns are conducted of cell-cell adhesion as reported in a recent study [Liu et al., 2010, PNAS, 107(22), 9944-9] for two cells seeded on an array of micro-posts. The micro-post array allows for the measurement of forces exerted by the cell and these show that the cell-cell tugging stress is a constant and independent of the cell-cell junction area. In the current study, we demonstrate that a material model which includes the under lying cellular processes of stress fibre contractility and adhesion formation can capture these results. The simulations explain the experimentally observed phenomena where by the cell-cell junction forces increase with junction size but the tractions exerted by the cell on the micro-post array are independent of the junction size. Link to paper|
Influence of spreading and contractility on cell detachment
|An active modelling framework incorporating actin cytoskeleton remodelling and contractility, combined with a cohesive zone model to simulate debonding at the cell–substrate interface, is implemented to investigate the increased resistance to detachment of highly spread chondrocytes from a substrate, as observed experimentally by Huang et al. (J. Orthop. Res. 21: 88–95, 2003). Spread cells with a flattened morphology and a larger adhesion area have a more highly developed actin cytoskeleton than rounded cells. Rounded cells provide less support for tension generated by the actin cytoskeleton. It is revealed that the more highly developed active contractile actin cytoskeleton of the spread cell increases the resistance to shear deformation, and subsequently increases the shear detachment force. Link to paper|
Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression
|A modified atomic force microscope is used to perform whole cell compression of osteoblasts. Compression tests are also performed on cells following the inhibition of the cell actin cytoskeleton using cytochalasin-D. An active bio-chemo-mechanical conputational model is employed to predict the active remodeling of the actin cytoskeleton. The model incorporates the myosin driven contractility of stress fibers via a muscle-like constitutive law. The passive mechanical properties, in parallel with active stress fiber contractility parameters, are determined for osteoblasts. Simulations reveal that the computational framework is capable of predicting changes in cell morphology and increased resistance to cell compression due to the contractility of the actin cytoskeleton. It is demonstrated that osteoblasts are highly contractile and that significant changes to the cell and nucleus geometries occur when stress fiber contractility is removed. Link to paper|