Cellular contractility and substrate elasticity: a numerical investigation of the actin cytoskeleton and cell adhesion
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Numerous experimental studies have established that cells can sense the stiffness of underlying substrates and have quantified the effect of substrate stiffness on stress fibre formation, focal adhesion area, cell traction, and cell shape. In order to capture such behaviour, the current study couples a mixed mode thermodynamic and mechanical framework that predicts focal adhesion formation and growth with a material model that predicts stress fibre formation, contractility, and dissociation in a fully 3D implementation. Simulations reveal that SF contractility plays a critical role in the substrate-dependent response of cells. Compliant substrates do not provide sufficient tension for stress fibre persistence, causing dissociation of stress fibres and lower focal adhesion formation. In contrast, cells on stiffer substrates are predicted to contain large amounts of dominant stress fibres. Different levels of cellular contractility representative of different cell phenotypes are found to alter the range of substrate stiffness that cause the most significant changes in stress fibre and focal adhesion formation. Furthermore, stress fibre and focal adhesion formation evolve as a cell spreads on a substrate and leading to the formation of bands of fibres leading from the cell periphery over the nucleus. Inhibiting the formation of FAs during cell spreading is found to limit stress fibre formation. The predictions of this mutually dependent material-interface framework are strongly supported by experimental observations of cells adhered to elastic substrates and offer insight into the inter-dependent biomechanical processes regulating stress fibre and focal adhesion formation.
KeywordsStress fibre contractility Focal adhesion formation Substrate elasticity Nucleus stress Finite element Active constitutive formulation
Funding support was provided by the Irish Research Council for Science, Engineering and Technology (IRCSET) postgraduate scholarship under the EMBARK initiative and by the Science Foundation Ireland Research Frontiers Programme (SFI-RFP/ENM1726). The authors acknowledge the SFI/ HEA Irish Centre for High-End Computing (ICHEC) for the provision of computational facilities and support.
- Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzur G, Sabanay I, Mahalu D, Safran S, Bershadsky A, Addadi L, Geiger B (2001) Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat Cell Biol 3(5):466–472. doi: 10.1038/35074532 CrossRefGoogle Scholar
- Broers JLV, Peeters EAG, Kuijpers HJH, Endert J, Bouten CVC, Oomens CWJ, Baaijens FPT, Ramaekers FCS (2004) Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies. Hum Mol Genet 13(21):2567–2580. doi: 10.1093/hmg/ddh295 CrossRefGoogle Scholar
- Danjo Y, Gipson IK (1998) Actin ‘purse string’ filaments are anchored by E-cadherin-mediated adherens junctions at the leading edge of the epithelial wound, providing coordinated cell movement. J Cell Sci 111(22):3323–3332Google Scholar
- De Santis G, Lennon A, Boschetti F, Verhegghe B, Verdonck P, Prendergast P (2011) How can cells sense the elasticity of a substrate?: an analysis using a cell tensegrity model. Eur Cells Mater 22:202–213Google Scholar
- Dowling EP, Ronan W, Ofek G, Deshpande VS, Athanasiou KA, McMeeking RM, McGarry JP (2012) The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: a computational and experimental investigation. J Roy Soc Interf 9(77):3469–3479. doi: 10.1098/rsif.2012.0428 CrossRefGoogle Scholar
- Ingber DE (1993) Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J Cell Sci 104:613–613Google Scholar
- Kaunas R, Hsu HJ, Deguchi S (2011) Sarcomeric model of stretch-induced stress fiber reorganization. Cell Health Cytoskelet 3:13–22Google Scholar
- Leckband D, Israelachvili J, Schmitt F, Knoll W (1992) Long-range attraction and molecular rearrangements in receptor-ligand interactions. Science (New York, NY) 255(5050):1419Google Scholar
- Pathak A, Deshpande VS, Evans AG, McMeeking RM (2012) Simulations of Cell Behavior on Substrates of Variegated Stiffness and Architecture. In: Holzapfel GA, Kuhl E (eds) Computer Models in Biomechanics. From Nano to Macro. Springer, The Netherlands, pp 25–41.Google Scholar
- Potter DA, Tirnauer JS, Janssen R, Croall DE, Hughes CN, Fiacco KA, Mier JW, Maki M, Herman IM (1998) Calpain regulates actin remodeling during cell spreading. J Cell Biol 141(3):647– 662Google Scholar
- Roberts SR, Knight MM, Lee DA, Bader DL (2001) Mechanical compression influences intracellular Ca2+ signaling in chondrocytes seeded in agarose constructs. J Appl Physiol 90(4):1385–1391Google Scholar