Plasma and cellular fibronectin: distinct and independent functions during tissue repair

Abstract

Fibronectin (FN) is a ubiquitous extracellular matrix (ECM) glycoprotein that plays vital roles during tissue repair. The plasma form of FN circulates in the blood, and upon tissue injury, is incorporated into fibrin clots to exert effects on platelet function and to mediate hemostasis. Cellular FN is then synthesized and assembled by cells as they migrate into the clot to reconstitute damaged tissue. The assembly of FN into a complex three-dimensional matrix during physiological repair plays a key role not only as a structural scaffold, but also as a regulator of cell function during this stage of tissue repair. FN fibrillogenesis is a complex, stepwise process that is strictly regulated by a multitude of factors. During fibrosis, there is excessive deposition of ECM, of which FN is one of the major components. Aberrant FN-matrix assembly is a major contributing factor to the switch from normal tissue repair to misregulated fibrosis. Understanding the mechanisms involved in FN assembly and how these interplay with cellular, fibrotic and immune responses may reveal targets for the future development of therapies to regulate aberrant tissue-repair processes.

Figure 1

Fibronectin (FN) and FN fragments. FN is composed of a series of FNI repeats (dark-gray boxes), FNII repeats (circles), conserved FNIII repeats (light-gray boxes) and alternatively spliced FNIII repeats (EDA).

Figure 2

Functions of plasma and cellular fibronectin (FN) during wound healing. The different forms of FN play distinct roles during the different stages of wound healing.

Figure 3

Stages of fibronectin (FN)-matrix assembly: initiation, unfolding and fibrillar assembly. (A) FN initiation involves interactions with cell-surface receptors: (i) FNI_1-5 within the 70-kDa domain binds to cell-surface receptors possibly including integrins, (ii) FNIII_9-10 binds to integrin α5β1, (iii) integrin activation by outside-in or inside-out signaling induces integrins to adopt a high-affinity state and allow FN binding and (iv) FNIII_12-14 binds to heparan sulfate proteoglycans (HSPGs). (B) FN unfolding: (i) FN binding to cell-surface receptors induces cyctoskeletal reorganization of the actin cytoskeleton and myosin II-dependent contractility that results in (ii) receptor clustering and translation. This causes the tethered FN molecules to become unfolded. (C) Unfolding of FN results in the exposure of FN binding sites that allow FN-FN intermolecular interactions to occur. The domains important for each step are circled and denoted.