Fibronectin-dependent collagen I deposition modulates the cell response to fibronectin

Abstract

munication between cells and the extracellular matrix (ECM) is critical for regulation of cell growth, survival, migration, and differentiation. Remodeling of the ECM can occur under normal physiological conditions, as a result of tissue injury, and in certain pathological conditions. ECM remodeling leads to alterations in ECM composition and organization that can alter many aspects of cell behavior, including cell migration. The cell migratory response varies depending on the type, amount, and organization of ECM molecules present, as well as the integrin and proteoglycan repertoire of the cells. We and others have shown that the deposition of several ECM molecules, including collagen types I and III, depends on the presence and stability of ECM fibronectin. Hence, the effect of fibronectin and fibronectin matrix on cell function may partially depend on its ability to direct the deposition of collagen in the ECM. In this study, we used collagen-binding fibronectin mutants and recombinant peptides that interfere with fibronectin-collagen binding to show that fibronectindependent collagen I deposition regulates the cell migratory response to fibronectin. These data show that the ability of fibronectin to organize other proteins in the ECM is an important aspect of fibronectin function and highlight the importance of understanding how interactions between ECM proteins influence cell behavior. extracellular matrix; contractility CELL FATE DECISIONS involving cell growth, differentiation, and survival rely on the ability of cells to coordinate diverse input from cytokines, growth factors, and extracellular matrix (ECM) molecules (3,89,94). The effects of ECM molecules on cell behavior are particularly complicated, since they depend on the mixture of ECM molecules that are present, the way the ECM proteins are organized and presented to cells, and the presence of proteases, protease inhibitors, and endocytic mechanisms that can alter the levels of ECM proteins and ECM degradation products. Understanding how ECM proteins act in concert to elicit biological effects is key to understanding how cell-ECM interactions maintain normal tissue function and influence the cell response to tissue injury.There is much data showing that mixtures of different ECM molecules can have effects distinct from that of a single ECM molecule. For example, coating dishes with a combination of tenascin C and fibronectin results in altered expression of matrix metalloproteinases (MMPs) (86), whereas addition of tenascin C to dishes coated with fibrin and fibronectin results in altered cytoskeletal organization (90) compared with cells seeded in the absence of tenascin C. The ability of fibronectin null cells to produce a fibronectin matrix is also dependent on the combination of matrix proteins present on the substrate (4). Furthermore, mixed collagen and fibronectin substrates have been shown to alter the response of endothelial cells to shear stress compared with their response to fibronectin alone (59). Similarly, addition of soluble matric...

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

“…In addition, progression of liver fibrosis has been found to correlate with a progressive increase in liver stiffness (11,69), and interestingly, an increase in liver stiffness has been shown to precede the pathological deposition of ECM proteins (70). Deposition of other ECM proteins such as collagen (20) depends on FN matrix. This could make FN a master regulator of stiffness-dependent ECM accumulation.…”

“…Type I collagen fibrils do not form in the absence of an FN matrix (20,31,32), and FN is believed to serve as a scaffold for collagen fibril formation (33). As shown in Fig.…”

“…Exposure of these FN-binding sites promotes intermolecular interactions and formation of fibrils that are initially soluble in the detergent deoxycholate (DOC) but are gradually and irreversibly converted into a stable, DOC-insoluble form that comprises the mature ECM. Whether cells increase FN fibril formation in response to sensing a rigid pericellular environment is an important question especially because FN assembly precedes and often seeds assembly of other ECM proteins such as collagen (20).…”

Collagenofibrotic Glomerulonephropathy with Fibronectin Deposition in a Dog

“…17 In our case, however, fibronectin deposition was localized in the subendothelial space and the GBM was fully formed. Therefore, because fibronectin also binds to type III collagen, 15 glomerular subendothelial accumulation of fibronectin might have been causally related to the accumulation of type III collagen.…”

Dynamic interactions between cells and their extracellular matrix mediate embryonic development

“…Interestingly, it has recently been shown that the ability of Fn to bind to collagen is critical for Fn -stimulated cell migration during wound healing (Sottile et al, 2007). Although this study was in vitro, the dynamic interaction between Fn-dependent collagen deposition and Fn-dependent cell migration highlights the need for integration of multiple ECM components when studying developmental processes.…”