Material-based regulation of the myofibroblast phenotype

• Published in: Biomaterials 2007-08, Vol.28 (23), p.3378-3387
• Main Authors: Cushing, Melinda C, Liao, Jo-Tsu, Jaeggli, Michael P, Anseth, Kristi S
• Format: Article
• Language: English
• Subjects: Actins - biosynthesis; Advanced Basic Science; Animals; Aortic Valve - cytology; Biocompatible Materials - chemistry; Cardiac valve tissue engineering; Cell signalling; Cells, Cultured; Collagen - biosynthesis; Culture Media, Serum-Free; Dentistry; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factor receptor; Fibroblasts - cytology; Fibroblasts - drug effects; Gene Expression Regulation - drug effects; Heparan Sulfate Proteoglycans - metabolism; Heparin; Heparin - pharmacology; Hydrogel; Hydrogel, Polyethylene Glycol Dimethacrylate - chemistry; MAPK; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; Muscle, Smooth - chemistry; Phenotype; Receptors, Fibroblast Growth Factor - metabolism; Signal Transduction - drug effects; Substrate Specificity; Swine; Tissue Engineering
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2007.04.005

Abstract Fibroblast growth factor receptor (FGFR) activation by basic fibroblast growth factor (FGF-2) serves to naturally repress the myofibroblast activation of valvular interstitial cells (VICs). Co-receptors for FGF-2, the heparan sulfate proteoglycans (HSPGs), are key participants in the formation of active FGF-2 signaling complexes. Bioactive environments regulating the myofibroblast phenotype were created by utilizing heparin glycosaminoglycan as a competitive inhibitor of HSPGs. First, soluble heparin was delivered to compete with cell-surface HSPG for the binding of FGF-2. Exogenous soluble heparin prevented serum-dependent activation of the classic mitogen-activated protein kinase (MAPK) and induced myofibroblast alpha smooth muscle actin ( α SMA) expression and collagen production. Next, heparin-functionalized hydrogel cell substrates were polymerized from vinyl-modified precursors and rendered adhesive through incorporation of RGDS peptide. Culture of VICs on heparin-modified gels induced α SMA expression and inhibited MAPK activity compared to control gel substrates lacking heparin. Additionally, heparin-functionalized gels continued to induce α SMA expression in serum-free culture conditions, suggesting that bioactivity was independent of exogenous soluble mediators. Biomaterial scaffolds targeting cell surface growth factor receptors are a promising new direction for regulating cell functions in tissue-engineering applications.