Therapeutic stem cell transplantation for muscular dystrophies

Principal Investigator:  Atsushi Asakura, Ph.D.

Duchenne Muscular Dystrophy (DMD) is a progressive disorder in which the absence of the protein dystrophin results in a loss of the dystrophin complex at the muscle membrane. In DMD muscle, muscle fibers are easily damaged and damaged muscle fibers degenerate. Normally, new fibers, recruited from muscle stem cells, regenerate in their place. However, regeneration is inefficient in DMD, so successive rounds of degeneration lead to a gradual replacement of muscle by connective tissue. Recent studies demonstrate that dystrophin is also normally detected in endothelial cells and the absence of dystrophin in these cells results in impaired blood flow. Therefore, blood flow regulation might be disturbed in DMD, possibly increasing muscle damage. Definitive treatment for muscular dystrophies will likely require the dystrophin complex to restore all affected muscle groups as well as the endothelium. Our long term objectives are to restore muscle fibers and vasculature using cell therapy. We have isolated myogenic-endothelial progenitors (MEPs) from adult skeletal muscle of mice, which can give rise to both myocytes and endothelial cells. Following intramuscular injection, MEPs were integrated into muscle fibers and vasculatures in regenerating mouse muscle. In addition, MEPs could be expanded ex vivo more than 10 fold while retaining their endothelial cell differentiation ability. In conclusion, MEPs are potentially useful for therapeutic stem cell transplantation for DMD. The hypothesis underlying the current proposal is that MEPs will engraft into regenerating muscle, differentiate into muscle fibers and endothelium, and thus provide an effective treatment of DMD. To test this, we examine whether MEPs can differentiate into myocytes and endothelial cells and engraft to a sufficiently large extent during muscle regeneration to enhance muscle function and blood flow in muscular dystrophy model mice. In addition, we examine whether large numbers of MEPs can be generated by ex vivo expansion for transplantation of larger doses and whether this increased dose enhances engraftment and functional correction of muscle in muscular dystrophy model mice?