Material-based regulation of the myofibroblast phenotype.
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 (alphaSMA) 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 alphaSMA expression and inhibited MAPK activity compared to control gel substrates lacking heparin. Additionally, heparin-functionalized gels continued to induce alphaSMA 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.
Cushing
Melinda C
MC
Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO 80309-0424, USA.
Liao
Jo-Tsu
JT
Jaeggli
Michael P
MP
Anseth
Kristi S
KS
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001021:Aortic Valve / Q000166:cytology; D001672:Biocompatible Materials / Q000737:chemistry; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009130:Muscle, Smooth / Q000737:chemistry; D010641:Phenotype; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D013552:Swine; D023822:Tissue Engineering
D000199:Actins; D001672:Biocompatible Materials; D016895:Culture Media, Serum-Free; D019812:Heparan Sulfate Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006493:Heparin; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases