Regulatory Mechanisms in the Chondrogenesis of Mesenchymal Progenitors: The Roles of Cyclic Tensile Loading and Cell-Matrix Interactions
Connelly, John Thomas
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Cartilage tissue engineering represents an exciting potential therapy for providing permanent and functional regeneration of healthy cartilage tissues, but these treatment options have yet to be successfully implemented in a clinical setting. One of the primary obstacles for cartilage engineering is obtaining a sufficient supply of cells capable of regenerating a functional cartilage matrix. Mesenchymal progenitors can easily be isolated from multiple tissues, expanded in vitro, and possess a chondrogenic potential, but it remains unclear what types or combinations of signals are required for lineage-specific differentiation and tissue maturation. The overall goal of this dissertation was to investigate how the coordination of biochemical stimuli with cues from mechanical forces and the extracellular matrix regulate the chondrogenesis of bone marrow stromal cells (BMSCs). These studies explored the potential for cyclic tensile loading and chondrogenic factors, TGF-1 and dexamethsone, to promote fibrochondrocyte-specific differentiation of BMSCs. The application of cyclic tensile displacements to cell-seeded fibrin constructs promoted fibrochondrocyte patterns of gene expression and the development of a fibrocartilage-like matrix. These responses were influenced by the specific loading conditions examined and the differentiation state of the BMSCs. Additionally, the roles of integrin adhesion and cytoskeletal organization in BMSC differentiation were examined within engineered hydrogels presenting controlled densities of biomimetic ligands. Adhesion to the arginine-glycine-aspartic acid (RGD) motif inhibited chondrogenesis in a density-dependent manner and was influenced by interactions with the f-actin cytoskeleton. Together, this research provided fundamental insights into the regulatory mechanisms involved in the chondrogenesis of mesenchymal progenitor cells.