page 909, De Bari et al. describe a cell- based therapeutic strategy for Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children. Although clinical studies are still a long way off, the results highlight the importance of secondary events in the pathogenesis of DMD and demonstrate the potential of a novel source of human adult stem cells.
DMD is caused by a lack of dystrophin at the sarcolemma of muscle fibers, resulting in irreversible degeneration of skeletal muscle once the satellite cells needed for regeneration have been depleted. Having identified a population of mesenchymal stem cells that can be cultured from the synovial membranes of adult human donors, the authors tested the muscle-regenerating capacity of the cells in two mouse models.
When transplanted into nude mice, the stem cells contribute to the formation of myofibers and give rise to functional satellite cells. Molecular markers suggest that the differentiation of the stem cells recapitulates embryonic myogenesis. Implanting the stem cells into mdx mice, a model of DMD, results in the appearance of human dystrophin at the sarcolemma and the expression of mouse mechano growth factor in skeletal muscle, a surrogate marker for the restoration of muscle contractility.
Direct replacement of dystrophin expression has yielded less than spectacular results. In contrast, the success of the stem cell approach reinforces the idea that the clinical progression of DMD is at least partly due to loss of stem cells—a secondary effect of the loss of dystrophin. Thus, restoring satellite cell populations, even while a patient retains a defect in dystrophin, could be an effective treatment strategy. The authors are now characterizing the existing synovial membrane–derived human stem cells in detail, in the hopes of identifying a cell population with predictable and reproducible biological behavior for use in human patients. Additional studies will focus on analyzing muscle function in mdx mice directly over long periods, rather than relying on surrogate markers. ▪