Although skeletal muscle accounts for a large fraction of the body mass, it is one of the least regenerative of tissues. Satellite cells, which reside within the basal lamina of mature skeletal muscle fibers, are capable of mitotic expansion thereby generating new adult myoblasts to effect local repair of injured or diseased muscle. Such adult myoblasts, however, are not capable of replacing large losses of muscle tissue that occur through injury or as a consequence of chronic muscle disease, such as Duchenne's muscular dystrophy. Even after in vitro enrichment and implantation into injured muscle sites, such adult myoblasts evidence little incorporation and integration into organized muscle tissue. Ideal cells that could be used in muscle replacement therapy should be capable of: (1) large mitotic expansion potential through stem cell activity; (2) morphogenetic capacity (involving complex intra-tissue and extra-tissue interactions); (3) migratory capacity (short and long distance). At present, neither a source of such cells nor an effective muscle replacement strategy is available. These qualities are possessed by the embryonic cells that build the muscle primordia of the body. During the previous 3 years of this project we have identified, Isolated and otherwise analyzed a novel class of embryonic muscle stem cells that we name mvogenic progenitor cells (MP cells). MP cells are distinct from satellite cells in their ability to undergo migration and morphogenetic movements. MP cells are distinct from their earlier embryonic counterparts, typically referred to as """"""""embryonic stem cells,"""""""" in that they are not multipotent but are developmentally restricted to the formation of skeletal muscle tissue only. Most importantly, after transplantation from one embryo to another, MP cells act in a semiautonomous fashion to generate organized muscle tissue, even under non-permissive conditons. Thus, MP cells retain intrinsic determined qualities that allow them to form muscle tissues even in localities that are inappropriate or even hostile. Thus, embryonic MP cells possess the qualities required for cells to be used for muscle replacement therapy. In the present proposal, we will isolate MP cells from avian embryos and analyze their cellular, tissue, and molecular properties. These studies will lead to a deeper understanding of the processes by which muscle tissue is formed in both normal and abnormal development. More important from a potential therapeutic point of view however, the properties discovered about MP cells from this study will provide a foundation for the engineering of their essential properties into other cells, such as satellite cells, for their potential use in myoblast transfer or other therapies.
