Molecular and Cellular Regulation of Stem Cells During Muscle Regeneration

Skeletal muscle is among the few adult tissues with the capacity to regenerate after injury. This is due to the resident stem cells within the muscle, the satellite cells. In the absence of injury, these stem cells remain quiescent and reside within their niche beneath the basement membrane adjacent to the myofiber. Upon muscle injury, satellite cells are activated and will proliferate, self renew, and differentiate into transiently amplifying myoblasts, which also self renew and give rise to differentiating myocytes. These myocytes will fuse to themselves and to the injured myofibers to repair muscle damage. While the cellular processes of muscle regeneration are understood, many questions remain. Despite similarities in their expression patterns and function, many characteristics are dissimilar between developmental myogenic precursors and satellite cells. Chapter 2 of this dissertation reviews what is known about the unique properties of these closely related cells, and Chapter 3 of this dissertation directly tests the requirement of satellite cells during muscle regeneration. In addition to the myogenic cells, many nonmuscle cells are involved in the process of muscle regeneration. Chapter 3 of this dissertation also shows that connective tissue fibroblasts prevent premature differentiation of satellite cells and are an important component of the satellite cell niche. One signaling pathway shown to regulate stem cells in other tissue contexts is the Wnt/beta-catenin pathway. Multiple studies describe the role of Wnt/beta-catenin signaling in muscle regeneration; however, there is no consensus as to the functional role of this signaling pathway in adult myogenesis. In Chapter 4 of this dissertation, the requirement for Wnt/beta-catenin in the satellite cells and their progeny is tested in vivo. Surprisingly, despite evidence that the Wnt/beta-catenin signaling pathway is active in myogenic cells during regeneration, satellite cells and their progeny do not require beta-catenin. Chapter 4 also discusses our results that show that extension of Wnt/beta-catenin signaling prolongs the time myogenic cells spend in the myoblast phase of regeneration. This dissertation demonstrates the importance of the connective tissue fibroblasts and also critically tests the function of the Wnt/beta-catenin signaling pathway in muscle regeneration.