Stem Cell-Based Therapy for Duchenne Muscular Dystrophy

In 1978, Partridge et al. first demonstrated that mouse myoblasts intramuscularly transplanted into recipient mice fuse with recipient myofibers. In 1989, the same research group showed that wild-type myoblasts successfully restored dystrophin expression in host mdx mice. Based on this report, several clinical trials of myoblast transfer for Duchenne muscular dystrophy (DMD) have been performed, but none has been successful in restoration of muscle function. Meanwhile, information about molecular regulation of satellite cells/myoblasts and cellular and molecular regulation of muscle regeneration has accumulated, and new types of stem cells with multipotency have been identified in skeletal muscle. The mesoangioblast is one such stem cell. Notably, mesoangioblasts have been demonstrated to be deliverable to damaged muscle by intra-arterial injection. In addition to skeletal muscle-resident stem cells, in 2007, Yamanaka and his colleagues reported the induction of embryonic stem (ES) cell-like pluripotent stem cells from human fibroblasts via the ectopic expression of SOX2, OCT3/4, KLF4, and c-MYC and named them “induced pluripotent stem cells (iPS cells).” The next year, generation of iPS cells from cells of patients with DMD was reported. To utilize iPS cells for regenerative medicine for muscular dystrophies, several protocols for derivation of skeletal muscle from human ES/iPS cells have been developed. Lastly, efficient genome-editing tools have emerged as a technology to obtain genetically corrected autologous cells. To make full use of these new tools in regenerative medicine, we need to understand how skeletal muscle stem cells are born, how they participate in regeneration of muscle fibers, and how the process is impaired in dystrophin-null muscle.