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Fibrous connective tissues provide mechanical support and frameworks for other tissues of the body and play an integral role in normal tissue physiology and pathology. Three-dimensional collagen matrices exhibit mechanical and structural features that resemble fibrous connective tissue and have become an important model system to study cell behavior in a tissue-like environment. This review focuses on motile and mechanical interactions between cells—especially fibroblasts—and collagen matrices. We describe several matrix contraction models, the interactions between fibroblasts and collagen fibrils at global and subcellular levels, unique features of mechanical feedback between cells and the matrix, and the impact of the cell-matrix tension state on cell morphology and mechanical behavior. We develop a conceptual framework to explain the balance between cell migration and collagen translocation including the concept of promigratory and procontractile growth factor environments. Finally, we review the significance of these concepts for the physiology of wound repair.
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Download Supplemental Figures and Tables as a PDF. Contents include: Supplemental Video 1: Time-lapse video microscopy of cell migration shows that in addition to cells migrating out of the inner matrix, collagen fibrils in the outer matrix translocate toward the interface between the outer and inner matrices. Download movie file (MOV) Supplemental Video 2: PDGF-stimulated migration occurs by repeated protrusion and retraction of dendritic processes with small tractional forces localized to the tips. Download movie file (MOV) Supplemental Video 3: Serum-stimulated migration results in larger and more sustained tractional forces at the leading edge and more pronounced rupture of cell-matrix adhesions at the rear, which results in elastic tail recoil and release of matrix tension. Download movie file (MOV) Supplemental Video 4: Bard and Hay introduced DIC imaging to visualize corneal embryonic fibroblast migration in situ and in collagen matrices. This approach allowed direct visualization of the local collagen fibril organization surrounding the cells. Improved optics and digital imaging now allow these processes to be studied with high temporal and spatial resolution. Download movie file (MOV) Supplemental Video 5: DIC analysis of green fluorescent protein (GFP)-zyxin expressing fibroblasts spreading on or within collagen matrices shows that new focal adhesions form at the tips of pseudopodia while existing adhesions move backward. Simultaneously, adhesions at the base of pseudopodia move toward those at the tip, resulting in a region of contractile-like shortening and matrix compression. Download movie file (MOV) Supplemental Video 6: Inhibiting Rho kinase results in extension of cell pseudopodia and reversible relaxation of cell-induced tension on the matrix. Download movie file (MOV) Supplemental Video 7: Inward tractional forces are generated as cell pseudopodia extend outward following treatment of corneal fibroblasts in restrained collagen matrices with PDGF. Download movie file (MOV) Supplemental Video 8: Reducing effective matrix stiffness by pushing toward the front of a cell results in rapid cellular shortening with corresponding matrix compression along the cell body, similar to the shortening produced by releasing one end of a rubber band that is under tension. Download movie file (MOV)