Development of Nascent Focal Adhesions in Spreading Cells

Abstract

Cell spreading provides one of the simplest configurations in which eukaryotic cells develop angular symmetry-breaking assemblies of mechanosensing and mechanotransducive organelles in preparation for cell differentiation and movement. By identifying the edge of the cell-ECM adhesion area as having an important role in mechanosensor complex aggregation, we consider the spatial patterns arising on this edge, within a 1D lattice model of the nearest-neighbour interaction between individual integrin-mediated mechanosensors. We obtain the Ginzburg-Landau free energy for this model and analyse the spectrum of spatial modes as the cell spreads and increases the contact area. We test the plausibility of our model by comparing its predictions for the azimuthal angular frequency of aggregation of mechanosensors into nascent focal adhesions (FAs) to observations of the paxillin distribution in spreading fibroblasts.STATEMENT OF SIGNIFICANCE. The topic of cell adhesion on substrates is very active, with numerous theoretical, experimental and computer simulation studies probing the mechanisms and signalling pathways of cell response to interacting with substrate. Integrin-based adhesion complexes are known to be the individual units of this process, and their dense aggregation into focal adhesions leads to cells developing asymmetry, polarity, and eventually -locomotion. Here we develop a theoretical model that suggests that physical interactions between individual adhesion complexes is the factor that defines the initial breaking of symmetry of the cell spreading on substrate, and predicts the characteristic wavelength of modulation above the critical size of adhesion area.

Transient Nascent Adhesion at the Initial Stage of Cell Adhesion Visualized on a Plasmonic Metasurface

“…Cells respond to the environment and/or external chemical and physical stimuli, leading to proliferation and differentiation. [1][2][3][4][5][6][7][8][9] The adhesion of cells to substrates is the initial step in determining cellular responses against biomaterials. Cell adhesion is known to depend on the surface properties of substrates and the preadsorption of extracellular matrix (ECM) proteins on the substrates.…”

“…[2,3,9,10] Cells that adhere to substrates start spreading (deforming to a flattened shape) by forming focal adhesions (FAs) that consist of multiprotein assemblies at the adhesion interface. [7,[11][12][13] FAs anchor cells to the substrate via the interaction between the integrin molecule of the cell membrane and the ECM, tension is generated in the actin filaments that form the cytoskeleton, and the cells stretch and proliferate. [7,10,14] When cells spread on sufficiently stiff substrates, bundles of actin filaments, called "stress fibers (SFs)," form and associate with FAs or further aggregate FAs and contribute to cell migration.…”

“…[7,[11][12][13] FAs anchor cells to the substrate via the interaction between the integrin molecule of the cell membrane and the ECM, tension is generated in the actin filaments that form the cytoskeleton, and the cells stretch and proliferate. [7,10,14] When cells spread on sufficiently stiff substrates, bundles of actin filaments, called "stress fibers (SFs)," form and associate with FAs or further aggregate FAs and contribute to cell migration. [7] FAs are also known as "mechanosensors" of the adhered substrate, as they are the site of force transmission of stress generated within the cytoskeleton and the ECM.…”

“…[7,10,14] When cells spread on sufficiently stiff substrates, bundles of actin filaments, called "stress fibers (SFs)," form and associate with FAs or further aggregate FAs and contribute to cell migration. [7] FAs are also known as "mechanosensors" of the adhered substrate, as they are the site of force transmission of stress generated within the cytoskeleton and the ECM. [10,15,16] FAs contribute to the differentiation of stem cells and are recognized as a research target in mechanobiology.…”

“…[8,[19][20][21][22][23] In such studies, the number of FAs is often counted to assess the cell affinity for the substrate. [7,16] As the latest achievement, the development of super-resolution microscopy enabled the visualization of "nascent" FAs (typically 250 nm in size), which are dot-like transient adhesions with a relatively short lifetime. [8] Nascent adhesion is composed of integrins, actin linkage molecules (talin and vinculin), and signaling molecules, similar to mature FAs.…”