Abstract
Cell adhesion is a key phenomenon that affects fundamental cellular processes such as morphology, migration, and differentiation. In the current study, 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). 3D finite element meshes of the round and spread cell geometries with the same material properties are created. It is demonstrated that 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; hence, a high level of dissociation is predicted. 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. These findings provide new insight into the link between cell geometry, cell contractility, and cell–substrate detachment.
Similar content being viewed by others
References
Brown, P. D., and P. D. Benya. Alterations in chondrocyte cytoskeletal architecture during phenotypic modulation by retinoic acid and dihydrocytochalasin B-induced reexpression. J. Cell Biol. 106:171–179, 1988.
Buckwalter, J., and H. Mankin. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr. Course Lect. 47:487, 1998.
Caille, N., O. Thoumine, Y. Tardy, and J.-. J. Meister. Contribution of the nucleus to the mechanical properties of endothelial cells. J. Biomech. 35:177–187, 2002.
Chen, C. S., J. L. Alonso, E. Ostuni, G. M. Whitesides, and D. E. Ingber. Cell shape provides global control of focal adhesion assembly. Biochem. Biophys. Res. Commun. 307:355–361, 2003.
Chen, J., J. Irianto, S. Inamdar, P. Pravincumar, D. A. Lee, D. L. Bader, and M. M. Knight. Cell mechanics, structure, and function are regulated by the stiffness of the three-dimensional microenvironment. Biophys. J. 103:1188–1197, 2012.
Cheng, Q., P. Liu, H. Gao, and Y. Zhang. A computational modeling for micropipette-manipulated cell detachment from a substrate mediated by receptor–ligand binding. J. Mech. Phys. Solids 57:205–220, 2009.
Chrzanowska-Wodnicka, M., and K. Burridge. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133:1403–1415, 1996.
Darling, E. M., and K. A. Athanasiou. Rapid phenotypic changes in passaged articular chondrocyte subpopulations. J. Orthop. Res. 23:425–432, 2005.
Deshpande, V. S., R. M. McMeeking, and A. G. Evans. A bio–chemo–mechanical model for cell contractility. Proc. Natl. Acad. Sci. 103:14015–14020, 2006.
Deshpande, V. S., M. Mrksich, R. M. McMeeking, and A. G. Evans. A bio–mechanical model for coupling cell contractility with focal adhesion formation. J. Mech. Phys. Solids 56:1484–1510, 2008.
Dowling, E. P., W. Ronan, and J. P. McGarry. Computational investigation of in situ chondrocyte deformation and actin cytoskeleton remodelling under physiological loading. Acta Biomater. 9:5943–5955, 2012.
Dowling, E. P., W. Ronan, G. Ofek, V. Deshpande, R. M. McMeeking, K. A. Athanasiou, and J. P. McGarry. 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 9:3469–3479, 2012.
Engler, A., L. Bacakova, C. Newman, A. Hategan, M. Griffin, and D. Discher. Substrate compliance versus ligand density in cell on gel responses. Biophys. J. 86:617–628, 2004.
Frenkel, S. R., R. M. Clancy, J. L. Ricci, P. E. Di Cesare, J. J. Rediske, and S. B. Abramson. Effects of nitric oxide on chondrocyte migration, adhesion, and cytoskeletal assembly. Arthritis Rheum. 39:1905–1912, 1996.
Genes, N. G., J. A. Rowley, D. J. Mooney, and L. J. Bonassar. Effect of substrate mechanics on chondrocyte adhesion to modified alginate surfaces. Arch. Biochem. Biophys. 422:161–167, 2004.
Haudenschild, D. R., J. Chen, N. Steklov, M. K. Lotz, and D. D. D’Lima. Characterization of the chondrocyte actin cytoskeleton in living three-dimensional culture: response to anabolic and catabolic stimuli. Mol. Cell. Biomech. 6:135–144, 2009.
Huang, W., A. J. H. Bahman, R. Torres, G. Lebaron, and K. A. Athanasiou. Temporal effects of cell adhesion on mechanical characteristics of the single chondrocyte. J. Orthop. Res. 21:88–95, 2003.
Idowu, B. D., M. M. Knight, D. L. Bader, and D. A. Lee. Confocal analysis of cytoskeletal organisation within isolated chondrocyte sub-populations cultured in agarose. Histochem. J. 32:165–174, 2000.
Ishaug-Riley, S. L., L. E. Okun, G. Prado, M. A. Applegate, and A. Ratcliffe. Human articular chondrocyte adhesion and proliferation on synthetic biodegradable polymer films. Biomaterials 20:2245–2256, 1999.
Jean, R. P., C. S. Chen, and A. A. Spector. Finite-element analysis of the adhesion–cytoskeleton–nucleus mechanotransduction pathway during endothelial cell rounding: axisymmetric model. J. Biomech. Eng. 127:594–600, 2005.
Knight, M. M., B. D. Idowu, D. A. Lee, and D. L. Bader. Temporal changes in cytoskeletal organisation within isolated chondrocytes quantified using a novel image analysis technique. Med. Biol. Eng. Comput. 39:397–404, 2001.
Knight, M. M., T. Toyoda, D. A. Lee, and D. L. Bader. Mechanical compression and hydrostatic pressure induce reversible changes in actin cytoskeletal organisation in chondrocytes in agarose. J. Biomech. 39:1547–1551, 2006.
Kurtis, M. S., B. P. Tu, O. A. Gaya, J. Mollenhauer, W. Knudson, R. F. Loeser, C. B. Knudson, and R. L. Sah. Mechanisms of chondrocyte adhesion to cartilage: role of β1-integrins, CD44, and annexin V. J. Orthop. Res. 19:1122–1130, 2006.
Leckband, D., and J. Israelachvili. Intermolecular forces in biology. Q. Rev. Biophys. 34:105–267, 2001.
Li, W. J., Y. J. Jiang, and R. S. Tuan. Chondrocyte phenotype in engineered fibrous matrix is regulated by fiber size. Tissue Eng. Part A 12:1775–1785, 2006.
Lyman, J. R., J. D. Chappell, T. I. Morales, S. S. Kelley, and G. M. Lee. Response of chondrocytes to local mechanical injury in an ex vivo model. Cartilage 3:58–69, 2012.
Máirtín, É. Ó., G. Parry, G. E. Beltz, and J. P. McGarry. Potential-based and non-potential-based cohesive zone formulations under mixed-mode separation and over-closure—part II: finite element applications. J. Mech. Phys. Solids, 2013.
Mallein-Gerin, F., R. Garrone, and M. Van der Rest. Proteoglycan and collagen synthesis are correlated with actin organization in dedifferentiating chondrocytes. Eur. J. Cell Biol. 56:364–373, 1991.
McGarry, J. P. Characterization of cell mechanical properties by computational modeling of parallel plate compression. Ann. Biomed. Eng. 37:2317–2325, 2009.
McGarry, J. P., É. Ó Máirtín, G. Parry, and G. E. Beltz. Potential-based and non-potential-based cohesive zone formulations under mixed-mode separation and over-closure. Part I: Theoretical analysis. J. Mech. Phys. Solids, 2013.
McGarry, J. P., J. Fu, M. T. Yang, C. S. Chen, R. M. McMeeking, A. G. Evans, and V. S. Deshpande. Simulation of the contractile response of cells on an array of micro-posts. Philos. Trans. R. Soc. A Math. Phys. Eng. Sci. 367:3477–3497, 2009.
McGarry, J. P., and P. E. McHugh. Modelling of in vitro chondrocyte detachment. J. Mech. Phys. Solids 56:1554–1565, 2008.
McGarry, J. P., B. P. Murphy, and P. E. McHugh. Computational mechanics modelling of cell–substrate contact during cyclic substrate deformation. J. Mech. Phys. Solids 53:2597–2637, 2005.
McGarry, J., and P. Prendergast. A three-dimensional finite element model of an adherent eukaryotic cell. Eur. Cell. Mater. 7:27–33, 2004.
Ofek, G., E. P. Dowling, R. M. Raphael, J. P. McGarry, and K. A. Athanasiou. Biomechanics of single chondrocytes under direct shear. Biomech. Model. Mechanobiol. 9:153–162, 2009.
Parker, K. K., A. L. Brock, C. Brangwynne, R. J. Mannix, N. Wang, E. Ostuni, N. A. Geisse, J. C. Adams, G. M. Whitesides, and D. E. Ingber. Directional control of lamellipodia extension by constraining cell shape and orienting cell tractional forces. FASEB J. 16:1195–1204, 2002.
Pathak, A., V. S. Deshpande, R. M. McMeeking, and A. G. Evans. The simulation of stress fibre and focal adhesion development in cells on patterned substrates. J. R. Soc. Interface 5:507–524, 2008.
Riveline, D., E. Zamir, N. Q. Balaban, U. S. Schwarz, T. Ishizaki, S. Narumiya, Z. Kam, B. Geiger, and A. D. Bershadsky. Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J. Cell Biol. 153:1175–1186, 2001.
Rodriguez, M. L., J. P. McGarry, and N. J. Sniadecki. Review on cell mechanics: experimental and modeling approaches. Appl. Mech. Rev. 65, 2013.
Ronan, W., V. Deshpande, R. M. McMeeking, and J. P. McGarry. Numerical investigation of the active role of the cytoskeleton in the compression resistance of cells. J. Mech. Behav. Biomed. Mater. 14:143–157, 2012.
Ronan, W., V. Deshpande, R. M. McMeeking, and J. P. McGarry. Cellular contractility and substrate elasticity: a numerical investigation of the actin cytoskeleton and cell adhesion. Biomech. Model. Mechanobiol. 2013. doi:10.1007/s10237-013-0506-z.
Ronan, W., P. McGarry, A. Pathak, V. Deshpande, and R. McMeeking. Simulation of the mechanical response of cells on micro-post substrates. J. Biomech. Eng. 135, 2013.
Schinagl, R. M., M. S. Kurtis, K. D. Ellis, S. Chien, and R. L. Sah. Effect of seeding duration on the strength of chondrocyte adhesion to articular cartilage. J. Orthop. Res. 17:121–129, 1999.
Tan, J. L., J. Tien, D. M. Pirone, D. S. Gray, K. Bhadriraju, and C. S. Chen. Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc. Natl. Acad. Sci. 100:1484–1489, 2003.
Thoumine, O., O. Cardoso, and J. J. Meister. Changes in the mechanical properties of fibroblasts during spreading: a micromanipulation study. Eur. Biophys. J. 28:222–234, 1999.
Weafer, P., W. Ronan, S. Jarvis, and J. McGarry. Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression. Bull. Math. Biol. 75:1284–1303, 2013.
Woods, A., G. Wang, and F. Beier. RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis. J. Biol. Chem. 280:11626–11634, 2005.
Yamamoto, A., S. Mishima, N. Maruyama, and M. Sumita. Quantitative evaluation of cell attachment to glass, polystyrene, and fibronectin-or collagen-coated polystyrene by measurement of cell adhesive shear force and cell detachment energy. J. Biomed. Mater. Res. Part A 50:114–124, 2000.
Yeung, T., P. C. Georges, L. A. Flanagan, B. Marg, M. Ortiz, M. Funaki, N. Zahir, W. Ming, V. Weaver, and P. A. Janmey. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskelet. 60:24–34, 2005.
Acknowledgments
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 wish to acknowledge the SFI/HEA Irish Centre for High-End Computing (ICHEC) for the provision of computational facilities and support. The authors would like to thank Prof. K.A. Athanasiou, Prof. V.S. Deshpande, Prof. R.M. McMeeking, and Dr. W. Ronan for helpful discussions and insights relating to this study.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Eric M. Darling oversaw the review of this article.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Dowling, E.P., McGarry, J.P. Influence of Spreading and Contractility on Cell Detachment. Ann Biomed Eng 42, 1037–1048 (2014). https://doi.org/10.1007/s10439-013-0965-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-013-0965-5