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PROGRAM | Materials Science & Engineering

Regulating Cell Phenotype and Function Using Custom-Designed Synthetic Matrices

By: Anitha Ravikrishnan Chair: Xinqiao Jia

ABSTRACT

The natural extracellular matrix serves as a mechanical platform for cells and influences basic cellular functions. Using custom-designed, synthetic matrices, I investigated how matrix composition and properties affect cell differentiation, tissue remodeling and regeneration.

In the first project, I investigated how the diameter of fibrous scaffolds affects epithelial-to-mesenchymal transition (EMT). I produced poly (e-caprolactone) (PCL)-based fibrous scaffolds with an average fiber diameter of 0.5 or 5.0 mm. I discovered that Madin-Darby Canine Kidney cells grown on 0.5-mm scaffolds adopted an epithelial phenotype and underwent EMT in the presence of a soluble EMT inducer. Contrarily, cells maintained on 5.0-mm substrates were more mesenchymal-like and did not respond to the EMT inducer. Therefore, fiber diameter is a potent regulator of cell phenotype.

In the second project, I investigated how matrix composition affects fibrogenesis. Fibrous scaffolds with a stiff PCL core (diameter: 3.8 mm) and a soft, hyaluronic acid (HA) hydrogel shell (thickness: 0.1 or 0.7 mm) were produced. I found that primary porcine vocal fold fibroblasts (PVFFs) cultured on fibers with a thin HA shell adopted a myofibroblast phenotype, whereas those maintained on fibers with a thick HA coating remained fibroblastic. Stimulation with a profibrotic growth factor, transforming growth factor β (TGFβ), promoted myofibroblastic differentiation of cells cultured on both substrates. However, inhibition of Rho-associated kinases significantly attenuated the expression of fibrotic markers by cells grown on fibers with 0.7-mm HA shell, but not the 0.1-mm counterpart. Thus, PVFFs sense the thick HA shell and shift away from myofibroblastic differentiation even in the presence of a soluble TGFb.

The goal of the third project is to engineer a physiologically relevant vocal fold cover. HA-based synthetic matrices of varying composition and stiffness were produced. I discovered that primary porcine vocal fold epithelial cells (PVFEs) cultured on gels with an elastic modulus of 2,000 Pa and presenting laminin 111-derived AG73 peptide matured into a stratified epithelium, consisting of a basal, proliferating cells, and upper, differentiated layers. Identifying matrix properties required for PVFE differentiation and stratification is a first step toward an engineered in vitro model of the human vocal fold.

In the final project, I investigated how distinct peptide signals mediate the differentiation of human salivary/stem progenitor cells (hS/PCs). HA-based hydrogels with covalently conjugated peptide derived from fibronectin (RGDSP), perlecan domain IV (TWSKV), and laminin 111 (YIGSR and IKVAV) were synthesized. I found that RGDSP and IKVAV signals promoted hS/PC differentiation to the ductal lineage, whereas TWSKV and YIGSR signals induced acinar differentiation. Identifying peptide ligands that induce hS/PC commitment to specific cell types found in the native gland helps pave the way for the development of an engineered salivary gland.

Overall this is work highlights the importance of biochemical, topographical and biomechanical signals of the extracellular matrix in regulating cellular interactions and fostering cell differentiation.

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