Material-based regulation of the myofibroblast phenotype

Area of Science:

• Biomaterials Science
• Cell Biology
• Tissue Engineering

Background:

• Fibroblast growth factor receptor (FGFR) activation by FGF-2 normally suppresses valvular interstitial cell (VIC) myofibroblast differentiation.
• Heparan sulfate proteoglycans (HSPGs) are crucial co-receptors for FGF-2, mediating its signaling complex formation.
• Myofibroblast activation in VICs is associated with pathological conditions like valvular heart disease.

Purpose of the Study:

• To investigate the use of heparin glycosaminoglycan as a competitive inhibitor of HSPGs to regulate VIC myofibroblast phenotype.
• To develop bioactive biomaterial scaffolds that modulate cell surface growth factor receptor signaling for tissue engineering applications.

Main Methods:

• Soluble heparin was used to compete with cell-surface HSPGs for FGF-2 binding, assessing its effect on VICs in serum-containing media.
• Heparin-functionalized hydrogel substrates were created and VICs were cultured on them to evaluate myofibroblast activation markers.
• Mitogen-activated protein kinase (MAPK) activity, alpha smooth muscle actin (alphaSMA) expression, and collagen production were measured.

Main Results:

• Exogenous soluble heparin inhibited serum-dependent MAPK activation, alphaSMA expression, and collagen production in VICs.
• VICs cultured on heparin-modified hydrogels exhibited increased alphaSMA expression and reduced MAPK activity compared to controls.
• Heparin-functionalized gels induced alphaSMA expression even in serum-free conditions, indicating sustained bioactivity.

Conclusions:

• Heparin can effectively inhibit FGF-2 signaling by competing with HSPGs, thereby repressing VIC myofibroblast activation.
• Heparin-functionalized biomaterial scaffolds represent a promising strategy for controlling cell phenotype in tissue engineering.
• Modulating cell surface growth factor receptor interactions offers a novel approach for therapeutic interventions in valvular diseases.