Abstract
Tendons are collagenous musculoskeletal tissues that transfer forces from muscle to bone to facilitate movement. Tendons are frequently injured, and the incidence of tendon injuries is increasing. They have limited intrinsic healing capacity, which results in poor healing and long-term loss of function. Additionally, there are few effective clinical treatments for restoring full function after a tendon injury. Tissue engineering and regenerative medicine strategies using mesenchymal stem cells (MSCs) have been explored as a new way to treat tendon injuries. However, a major challenge is a limited understanding of the factors that direct tendon formation and the differentiation of stem cells toward the tendon lineage (e.g., tenogenesis). A deeper understanding of the factors influencing stem cell fate and the ability to precisely guide their differentiation are needed before stem cells can be used therapeutically in regenerative treatments for tendon injuries. To address this gap in knowledge, the overall goal of this dissertation is to explore the mechanical and cellular factors involved in tendon formation and tenogenic stem cell differentiation. To address this goal, functional formation of neonatal tendons was explored during the onset of locomotor activity to determine impacts of mechanical loading on tendon development. Unique features that distinguish the functional development of distinct tendon types were identified and related to mechanical stimulation. To explore cellular factors, MSCs were treated with a developmentally inspired biochemical, transforming growth factor (TGF)2, to induce tenogenesis. Tenogenesis in MSCs was found to regulate specific cell-cell junction proteins as well as proceed through novel signaling pathways. Overall, results of the studies contribute to our understanding of tendon development, with the ultimate objective of informing and improving regenerative therapies to treat tendon injury and disease.