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Cell Spreading and Focal Adhesion Dynamics Are Regulated by Spacing of Integrin Ligands

Elisabetta Ada Cavalcanti-Adam ^*, Tova Volberg , Alexandre Micoulet ^*, Horst Kessler , Benjamin Geiger  and Joachim Pius Spatz ^*

^* Max-Planck-Institute for Metals Research, Department of New Materials and Biosystems, Stuttgart, Germany, and University of Heidelberg, Department of Biophysical Chemistry, Heidelberg, Germany; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel; and Technical University of Munich, Institute for Organic Chemistry and Biochemistry, Garching, Germany

Correspondence: Address reprint requests to Elisabetta Ada Cavalcanti-Adam, University of Heidelberg, Dept. of Biophysical Chemistry, INF 253, 69120 Heidelberg, Germany. Tel.: 49-6221-544232; Fax: 49-6221-544950; E-mail: ada.cavalcanti-adam{at}urz.uni-heidelberg.de.

Integrin-mediated adhesion is regulated by multiple features of the adhesive surface, including its chemical composition, topography, and physical properties. In this study we investigated integrin lateral clustering, as a mechanism to control integrin functions, by characterizing the effect of nanoscale variations in the spacing between adhesive RGD ligands on cell spreading, migration, and focal adhesion dynamics. For this purpose, we used nanopatterned surfaces, containing RGD-biofunctionalized gold dots, surrounded by passivated gaps. By varying the spacing between the dots, we modulated the clustering of the associated integrins. We show that cell-surface attachment is not sensitive to pattern density, whereas the formation of stable focal adhesions and persistent spreading is. Thus cells plated on a 108-nm-spaced pattern exhibit delayed spreading with repeated protrusion-retraction cycles compared to cells growing on a 58-nm pattern. Cell motility on these surfaces is erratic and nonpersistent, leaving thin membrane tethers bound to the RGD pattern. Dynamic molecular profiling indicated that the adhesion sites formed with the 108-nm pattern undergo rapid turnover and contain reduced levels of zyxin. These findings indicate that a critical RGD density is essential for the establishment of mature and stable integrin adhesions, which, in turn, induce efficient cell spreading and formation of focal adhesions.

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