A major problem confronting craniofacial repair is the difficulty in restoring soft-tissue function and contour in patients with anomalies including hemifacial microsomia, unilateral clefts of lips and palate as well as defects in the TMJ. In particular, repair of skeletal muscle defects is limited by difficulty in its transplantation and survival. A logical approach is to use existing population of muscle satellite cells which are quiescent undifferentiated precursors found beneath the basement membrane of mature muscle fibers. Following injury, activated satellite cells regenerate muscle after initiating a differentiation program whereby they migrate along laminin-rich basement membrane, proliferate, differentiate, and integrate with preexisting myofibers. Recent evidence supports the notion that satellite cells are heterogeneous and have stem cell potential. We have shown that the laminin-binding alpha 7 integrin, which is important for myoblast migration, is expressed on a subset of satellite cells and is upregulated in terminally differentiated myotubes. In this application, we propose to examine the potential of using alpha 7-positive human satellite cells for direct repair of muscle defects. We will explore the hypothesis that alpha 7 expressing satellite cells are pluripotent stem cells capable of regenerating skeletal muscle and other tissue such as bone. The proposal represents three aims.
In aim 1 we will characterize human muscle-derived satellite cells and correlate expression of alpha 7 integrin with their differentiation potential for skeletal muscle and other tissue lineages.
Aim 2 will determine the expression and function of the alpha 7 integrin during human skeletal muscle development.
Aim 3 is focused on the use of alpha 7-expressing human skeletal muscle stem cells to engineer in vitro three-dimensional skeletal muscle myofibers. These studies will form the basis for strategies that target the mechanical reintegration of regenerating myotubes to repair orofacial muscle structures using adult skeletal muscle stem cells.
