Complex Mechanics of Constrained Connective Tissue Matrices and their Impact on Cellular Mechanosensation

Physical interactions of cells with matrix microenvironments are critical steps in many cellular processes such as mechanosensation and metastatic invasion. Mechanosensory processes are strongly influenced by the composition and mechanical properties of the matrix, which in turn determines cell behavior. Several experimental strategies use homogeneous scaffolds to study cell behavior as a function of matrix microstructures. However, native matrix structures are highly heterogeneous in their organization and composition, which complicates understanding and definition of fundamental elements of mechanosensation. Accordingly, the sensory mechanisms used by cells to interpret matrix complexities, such as tissue boundaries, remain elusive. I developed a new model system to examine how lateral physical boundaries interfere with cell-induced compaction and remodeling of collagen and how these processes drive cell extension formation. The length and number of cell extensions were dependent on the distance of the cell from the physical boundaries. In the absence of physical boundaries, the resistance of thin collagen matrices to cell-generated forces was dependent on deformation rate. At rates similar to cell-induced deformations, native collagen matrices exhibited pronounced inelastic behavior, which in turn reduced tension in the network. Thus strain rate-dependent inelastic properties of collagen matrices may strongly influence cell-matrix interactions and matrix remodeling. Further, I determined that the actin cross-linking protein filamin A is required for cell-induced maintenance of tension and matrix compaction when resisted by physical boundaries. My findings underline the complex mechanics and structures of connective tissue matrices as determinants of cellular mechanosensation.Ph.D