Fibronectin Interaction and Enhancement of Growth Factors: Importance for Wound Healing

Abstract

Significance: This critical review focuses on interactions between cells, fibronectin (FN), and growth factors (GF). Recent Advances: Initially, the extracellular matrix (ECM) was thought to serve simply as a reservoir for GFs that would be released as soluble ligands during proteolytic degradation of ECM. This view was rather quickly extended by the observation that ECM could concentrate GFs to the pericellular matrix for more efficient presentation to cell surface receptors. However, recent reports support much more complex interactions among GFs and ECM molecules, particularly FN, and the way these interactions can fine-tune cell responses to the microenvironment. Critical Issues: Wounds that are unable to synthesize and sustain a functional ECM cannot optimally benefit from endogenous or exogenous GFs. Therefore, GF treatments have recently focused on utilizing ECM molecules as delivery vehicles. Thus, ECM can influence GF stability and activity, and GFs can modulate the ECM activity. Hence, both individually and together, ECM and GFs modulate cells that in turn control the type and level of GFs and ECM in the pericellular environment that ultimately results in new tissue generation. Although many ECM components are important for optimal tissue regeneration and wound healing, FN stands out as absolutely critical not only for wound healing and tissue regeneration but also for embryogenesis and morphogenesis. Future Directions: Understanding ECM/GF interactions will greatly facilitate our understanding of normal wound repair and regeneration, the failure of wounds to heal, and how the latter can be salvaged with proper ECM/GF combinations.

Richard A.F. Clark, MD

Figure 1.

Schematics of FN and the FN first type III repeat that contains P12. (a) FN schematic showing type I repeats as small rectangles, type II repeats as ovals, and type III repeats as large rectangles. Arrows indicate locations of P12 peptide residues in the first type III repeat (FNIII₁) and central cell-binding domain RGD residues in the 10th type III repeat (FNIII₁₀). (b) Structural schematic showing the immunoglobulin sandwich β-pleated sheet secondary structure and location of P12 residues. FN, fibronectin (from Markus Seeliger, PhD, Department of Pharmacological Sciences, with permission). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

P12 intravenous infusion 1 and 24 h after the burn inhibited injury progression in the rat hot comb burn model. (a and b) Burns at 7 days after injury without treatment. (c and d) Burns at 7 days after injury in animals that had been treated with 10 mg/kg P12. (e) Necrotic interspaces 2, 5, and 7 days after injury in rats treated or not treated with P12. (f) Necrotic interspaces 7 days after injury determined by histologic analysis. 0, infusion with lactated Ringer's buffer. Variance of interspace necrosis among rats within a specific treatment arm was no more than variance among interspaces on a given rat; therefore, interspace data for all five rats per treatment arm were pooled. n=30 interspaces (six interspaces/rat) in five rats per treatment arm. Bar=10 mm. Reprinted by permission from Lin et al. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

P12 rescued PDGF survival activity in CHC knockdown and dynamin-inhibited AHDF. (a) CHC siRNA was employed to knock down CHC expression in AHDF cells. The protein level dropped significantly after two consecutive transfections (36 h apart) with Hiperfect transfection reagents. (b) Mock cells were treated with 1 nM PDGF-BB±10 μM P12 (sP12) in HBSS for 3 days, and cell metabolism was measured with the XTT assay. Experiment was repeated thrice (asterisk, p<0.05 compared to PDGF alone, n=6). Error bar indicates SD. (c) CHC knockdown cells were treated with 1 nM PDGF-BB±10 μM P12 (sP12) in HBSS for 3 days, and cell metabolism was measured with the XTT assay. Experiment was repeated thrice (asterisk, p<0.05 compared to PDGF alone, n=6). Mean±SD. (d) AHDFs were preincubated for 1 h in a serum-free medium containing 80 μM dynasore, a dynamin inhibitor, and then treated with 1 nM PDGF-BB±10 μM P12 in HBSS. Western blots were performed with antibodies against phospho-Akt, phospho-JNK, phospho-ERK1/2, phospho-SHP2, and elF4e. GAPDH was used as a loading control. Data are representative of three independent experiments. AHDF, adult human dermal fibroblast; CHC, clatherin heavy chain; HBSS, Hank's balanced salt solution; PDGF, platelet-derived growth factor. Reprinted by permission from Zhu et al.

Figure 4.

FN matrix or peptides enhance GF activity on tissue cells to enhance new tissue formation or tissue remodeling. FN can influence GF stability and activity, and GFs can modulate FN activity. Hence, both individually and together, FN and GFs modulate cells that in turn control the type and level of GFs and ECM in the pericellular environment, which ultimately results in new tissue generation. ECM, extracellular matrix; GF, growth factor.