In nested collagen matrices, human fibroblasts migrate from cell-containing dermal equivalents into surrounding cell-free outer matrices. Time-lapse microscopy showed that in addition to cell migration, collagen fibril flow occurred in the outer matrix toward the interface with the dermal equivalent. Features of this flow suggested that it depends on the same cell motile machinery that normally results in cell migration. Collagen fibril flow was capable of producing large-scale tissue translocation as shown by closure of a ϳ1-mm gap between paired dermal equivalents in floating, nested collagen matrices. Our findings demonstrate that when fibroblasts interact with collagen matrices, tractional force exerted by the cells can couple to matrix translocation as well as to cell migration.
INTRODUCTIONCell migration depends on the multistep process of cell extension, adhesion, exertion of backward tractional force, and tail retraction (Lauffenburger and Horwitz, 1996;Mitchison and Cramer, 1996;Galbraith and Sheetz, 1997;Beningo et al., 2001;Ridley et al., 2003). The extensive body of research underlying the multistep model is based on studies with tissue cells on extracellular matrix (ECM)-coated planar surfaces including rigid materials such as glass or plastic coverslips as well as flexible materials such as polyacrylamide. On ECM-coated planar surfaces, cells can modulate their cytoskeletal function and adhesion strength in response to surface mechanics (Balaban et al., 2001;Discher et al., 2005;Ingber, 2006;Vogel and Sheetz, 2006). However, adsorbed or covalently attached ECM molecules tend to be held in register with each other with little capacity to undergo cell-mediated mechanical and molecular reorganization.Type 1 collagen is the major protein component of fibrous connective tissues. These connective tissues provide mechanical support and frameworks throughout the body, and fibroblasts are the cell type primarily responsible for their biosynthesis and remodeling. Three-dimensional (3D) matrices prepared with type I collagen exhibit mechanical properties that resemble connective tissue (Barocas et al., 1995;Wakatsuki et al., 2000;Roeder et al., 2002;Silver et al., 2002;Ahlfors and Billiar, 2007). Unlike ECM-coated material surfaces, fibroblasts can mechanically remodel collagen matrices both locally and globally (Brown et al., 1998;Tomasek et al., 2002;Grinnell, 2003;Petroll, 2004; Tranquillo, 1999Such mechanical remodeling of connective tissue ECM is believed to be important for tissue homeostasis (Silver et al., 2002;Wiig et al., 2003;Goldsmith et al., 2004;Langevin et al., 2004), aging (Varani et al., 2004), repair (Tonnesen et al., 2000Tomasek et al., 2002;Grinnell, 2003), fibrosis (Eckes et al., 2000;Desmouliere et al., 2005), and tumorigenesis (Beacham and Cukierman, 2005;Gaggioli et al., 2007;Yamada and Cukierman, 2007).Cells interacting with 3D collagen matrices exhibit distinct patterns of cell signaling (Cukierman et al., 2002;Wozniak et al., 2003;Beningo et al., 2004;Rhee et al., 2007) and increa...