It is well known that ECM plays a central role in microenvironmental control of cell motility based on its ability to chemically mediate cell adhesion. In addition, capillary endothelial cells must increase ECM degradation to initiate cell outgrowth and also must maintain ongoing ECM synthesis and deposition to sustain progressive cell migration during both angiogenesis and healing of large vessel endothelial monolayers. Importantly, recent work has revealed that the physical properties of the ECM, including its surface topography and mechanical compliance, also can significantly impact cell movement.
Compared with cells on rigid ECM substrates, cells on flexible substrates coated with the same ECM protein display increased rates of both lamellipodial activity (protrusion and retraction) and locomotion. Cells also prefer to move from regions of low to high mechanical rigidity. In addition, they move faster along edges of adhesives surfaces than in their central regions, and along microengineered grooves or thin lines than on flat ECM substrates. Furthermore, when individual cells are constrained to polygonal ECM-coated adhesive islands with angular edges (e.g., squares, triangles, pentagons, hexagons, trapezoids), they preferentially extend lamellipodia and filopodia from their corners. Thus, cells apparently can sense micrometer-scale changes in topography and subtle alterations in ECM mechanics, and they respond by changing both their cytoskeleton and migratory behavior. This knowledge could have important implications for engineering of artificial matrices for tissue engineering applications.
Studies of endothelial cell clusters cultured in a three-dimensional collagen gel have demonstrated directly that force application can promote capillary outgrowth. These experiments also showed that matrix-transduced tensional forces in stretched collagen gels are sufficient to control directional outgrowth as the growing capillaries extend along the tension field lines that stretch between neighboring cells. part of this response is based on the ability of the outgrowing endothelial cells to sense and respond to the direction of ECM fibrils that become aligned by the cell-generated forces.
The mechanism by which changes in ECM mechanics influence cell motility is less clear, largely because it has been difficult to study this process until recent years. Qualitative analysis of the traction forces exerted by migrating cells was first carried out by observing the pattern of wrinkles produced by fibroblasts cultured on deformable substrates (e.g., fibrin clots, collagen gels, silicon rubber substrates). Since that time, increasingly sophisticated methodologies have improved the quantification and spatiotemporal resolution of cell-based forces. For example, polyacrylamide gels with different degrees of cross-linking now allow substrate stiffness to be varied as an independent parameter in cell culture studies. The added use of fluorescent microbeads embedded in the gels as fiducial markers permits the direct quantitation of traction forces that are exerted by adherent cells. Combination of this method of "traction force microscopy" with micropatterning techniques also has allowed control of the position where cells exert these tractional forces, as well as analysis of the impact of varying this position on cell behavior.
These techniques have generated new and sometimes surprising insights. For example, it has recently been demonstrated that the small nascent focal adhesion complexes at the leading edge of a cell can exert stronger traction forces than larger, more mature focal adhesion plaques. In individual cells that are physically constrained to single square ECM adhesive islands, the localized distribution of focal adhesions corresponds precisely to the corner regions where the cell exerts greatest tractional forces on the substrate, deposits ECM (fibronectin) fibrils, and extends new migratory processes (lamellipodia and filopodia). Moreover, lamellipodia extension can be inhibited by dissipating cytoskeletal tension generation.
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