(275e) Computational Investigation of How Integrin Clustering Affects Cell Adhesion and Migration

Integrins are transmembrane proteins that bind extra-cellular matrix (ECM) proteins to facilitate cell adhesion and migration, and a variety of pathologies have been linked to problems with integrin function [1, 2]. Because integrins function by clustering at points of contact between cells and the ECM, integrin clustering potentially influences many aspects of cell function [3]; however, we currently lack a framework for systematically characterizing the effects of integrin activation states and ECM properties on integrin cluster formation.

In this work, we describe a reaction-diffusion model for integrin clustering, and discuss how it may be used to explore ways in which integrins modulate integrin cluster properties such as cluster shape, size, and formation dynamics. Our model represents integrins by three model states: unbound, bound, and clustered, and their reactivity is described by dimensionless parameters representing integrin activity characteristics, such as affinity and avidity, allowing us to infer how integrin activity directly affects integrin clustering. Because the integrin cluster properties described by the model are directly related to adhesion strength [4] and cell migration speed, we can use the model to understand how different integrin properties affect cell behavior, and how we may manipulate integrin and ECM properties to achieve desired cell adhesion and migration responses. Our results indicate that different combinations of integrin properties and ECM properties lead to integrin clusters with varying capacity for force transduction, given the same extent of integrin binding. Model simulations indicate that patterned ECM surfaces and fast integrin clustering result in integrin clusters that may be capable of transferring adhesive forces more effectively than non-patterned surfaces or slower-clustering integrins. Our results also suggest that ECM patterns and integrin properties can affect cell migration by controlling integrin cluster turnover, which affects cell migration speed. This insight into how integrin and ECM properties control integrin clustering may be used to control cell adhesion and migration on biomaterials by creating material design criteria based on optimum conditions for different cell types as a function of their integrin properties.

[1] Wozniak MA et al. Focal adhesion regulation of cell behavior. (2004) Biochim Biophys Acta 1692, 103-119.

[2] Wehrle-Haller B and Imhof BA, Integrin-dependent pathologies. (2003 ) J Pathol 200, 481-487.

[3] Miyamoto S et al. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. (1995) J Cell Biol 131, 791-805.

[4] Ward, M.D., and D.A. Hammer (1993) A theoretical analysis for the effect of focal contact formation on cell-substrate attachment strength. Biophys J. 64, 936-959.