Fibronectin matrix assembly enhances adhesion-dependent cell growth

ABSTRACT Cell growth control in non-transformed cells depends, in part, on adhesive interactions with the extracellular matrix. Following injury, excess or altered fibronectin deposition into the extracellular matrix may contribute to the pathogenesis of fibrosis and atherosclerosis by triggering changes in specific cell functions associated with wound repair, including cell proliferation and migration. To assess the role of fibronectin polymerization on cell growth, we isolated mouse embryonic cells that lack endogenous fibronectin (fibronectin-null cells) and established them in culture under serum-free conditions. These fibronectin-null cells do not produce any detectable fibronectin, but are capable of assembling a fibronectin matrix when cultured in the presence of exogenously added fibronectin. Our data indicate that adhesion-dependent growth in fibronectin-null cells is dramatically increased (>2-5×) by culturing cells in the presence of fibronectin. This fibronectin-induced cell growth was blocked by inhibiting fibronectin matrix assembly. Arg-Gly-Asp peptides or fragments of fibronectin that contain the Arg-Gly-Asp cell binding site promoted clustering of the α5β1 integrin in focal adhesions, but did not enhance cell growth. These data indicate that the polymerization of fibronectin into the extracellular matrix positively regulates cell growth, and that occupancy and clustering of fibronectin-binding integrins alone are not sufficient to trigger increased cell growth.