Fibronectin peptides in cell migration and wound repair.

a serious clinical problem; for example, decubitus and leg ulcers afflict roughly 5 million people in the US alone. Normal wound repair depends on molecules like fibronectin to promote cell adhesion and migration (1). This large adhesive glycoprotein provides a crucial substrate for many forms of cell migration , such as in embryonic migratory pathways and in the provisional matrix of healing wounds. Besides acting as a substrate, fibronectin also has certain proteolytic fragments that can promote chemotactic migration (e.g., see ref. 2), and fibronectin or its fragments can also activate integrin signaling (reviewed in refs. 3, 4). Because fibro-nectin augments cell migration, ideas for stimulating wound repair have included soaking wound dressings in fibronectin, providing fibronectin in eye drops, and developing synthetic polymeric substrates that contain biologically active fragments of the fibronectin sequence. A novel approach reported by Livant et al. in this issue of JCI (5) involves stimulating wound repair with a specific fibronectin peptide. This study reports intriguing findings that differ conceptually from the prior literature on fibronectin peptides. It describes a fibronectin peptide with unexpectedly high apparent affinity, an unusual mechanism of action, and high efficacy in vivo. These results appear to challenge current thinking in the field but, if correct, could lead to novel therapies for wounds. Fibronectin has nearly a dozen regions termed " cell-binding sites " that can be recognized and bound by cell-surface integrins (e.g., see ref. 6). These sites, including the four examples shown in Figure 1, can be reproduced as biologically active short pep-tides. When presented to cells as a peptide, a cell-binding site of fibronectin can function in several different ways (Figure 2): (a) It can mimic the intact protein as a substrate for migration. For example, if the peptide is adsorbed to a surface or attached covalently to a carrier molecule, it can be bound by a cell-surface integrin, which can mediate direct cell adhesion or cell migration. (b) The peptide can serve as a competitive inhibitor. When added in solution, the functional peptide can bind to the receptor and competitively inhibit binding of an adhesion molecule, thereby blocking adhesion and migration. (c) Binding of fibronectin peptides can augment integrin signaling (7) and can induce expression of collagenase or activate cell-to-cell adhesiveness in particular cell types (8–10). These pep-tides are generally thought to mimic activity seen in the intact fibronectin molecule, and their activities are generally significantly lower …