Transforming Growth Factor β, Bone Morphogenetic Protein, and Vascular Endothelial Growth Factor Mediate Phenotype Maturation and Tissue Remodeling by Embryonic Valve Progenitor Cells: Relevance for Heart Valve Tissue Engineering

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Abstract
Despite years of research, limited understanding of heart valve cell and tissue biology remains a key impediment to valvular tissue engineering progress. Heart valves rapidly evolve structural and cellular composition naturally during embryonic development, which suggests that mimicking these signaling events could advance engineered valve tissue research. Many inductive factors participate in the initial endocardial to mesenchymal transformation event necessary to form the prevalvular cushion, but far less is known about the regulation of cushion remodeling into fibrous leaflets and the associated maturation of valvular progenitors into fibroblasts. In this study, we combine in vitro three-dimensional tissue-engineered models of embryonic valvular remodeling with in vivo analysis to determine the roles of three prominent growth factors during avian mitral valvulogenesis. We show that transforming growth factor-β3 (TGFβ3), bone morphogenetic protein 2 (BMP2), and vascular endothelial growth factor A (VEGFA) are expressed in spatiotemporally distinct patterns and at significantly different levels within remodeling embryonic valves in vivo. We then establish dose-dependent functional roles for each growth factor in 3D cultured embryonic valve progenitor cells. TGFβ3 induced cell migration, invasion, and matrix condensation; BMP2 induced invasion. VEGFA inhibited invasion but increased migration. Finally, we determine that TGFβ3 induced myofibroblastic differentiation in a dose-dependent manner, whereas VEGFA and BMP2 did not. Collectively, these findings frame a naturally derived blueprint for controlling valvulogenic remodeling and phenotype maturation, which can be integrated into clinically needed regenerative strategies for heart valve disease and to accelerate the development of engineered tissue valves.