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NIH Symposium: Challenges & Promise of Cell-Based Therapies
May 6, 2008
Natcher Conference Center
NIH Main Campus, Bethesda, Maryland

Session 3: Musculoskeletal Disorders

Moderator: Pamela Robey, Ph.D.; National Institute of Dental and Craniofacial Research, NIH

Stem Cells and Muscular Dystrophy
Terence A. Partridge, Ph.D.; Children’s National Medical Center

Dr. Partridge began by discussing the properties of satellite cells, which reside on the surface of muscle fibers. These cells are involved in myonuclear turnover and the growth, repair, and regeneration of muscle tissue; as such, they were initially thought to be the stem cells for muscle tissue. Adult skeletal muscle regenerates within ten days, with the majority of the cellular regeneration taking place between days 2 and 5. Muscular dystrophy (MD) is caused by mutations in the dystrophin gene; defects in or the absence of the gene lead to disassembly of the muscle’s basement membrane protein complex. It has been proposed that satellite cells could be used in myoblast transplantation to improve regeneration of muscle tissue. While transplanted myoblasts have been shown to contribute to muscle regeneration, transplantation leads to localization and produces rapid cell death. Moreover, human satellite cells can undergo limited numbers of divisions in vitro because of telomeric shortening during cell division.

Victims of MD have a paucity of satellite cells, and grafted satellite cells have the potential to form large amounts of muscle tissue. For example, as few as seven satellite cells on a single myofiber can give rise to more than 20,000 myonuclei. Thus, fiber-graft experiments have indicated that the satellite cell compartment contains a robustly regenerative population that can replace itself in addition to generating muscle. Moreover, the cells can sustain several rounds of repeated regeneration. However, the satellite cell compartment loses most of these properties when separated from the muscle fiber, and these stem-like properties are observed only in a pre-irradiated environment. These results suggest that a different cell type may lead to regeneration; additional cell types may be present that have more “stemness” than the satellite cell. Regardless of the number of cell types that may be involved in regeneration, myoblast transplantation nonetheless remains ineffective due to massive post-transplant cell death, poor proliferation of transplanted cells, a lack of motility of transplanted cells, and rejection of mismatched donor cells.

Muscular dystrophy is characterized by fibrosis that results from collagen deposition, a process in which satellite cells are implicated. However, vessel-associated stem cells such as the pericyte-derived mesangioblast display general stem functions and can be delivered diffusively via the vascular route. Expansion in culture is required of the cells for myogenicity, and by adulthood, the cells have a limit of approximately 20 cell divisions. These cells do not replace satellite cells, and their precursors do not appear to be involved in normal myogenesis. Based on these characteristics, mesangioblasts appear to be a more appropriate cell population for therapy of MD. By contrast, the satellite cell displays tissue-specific stem functions. These cells and their progeny have limited migratory capacity, and expansion in culture diminishes their myogenicity. Finally, their involvement in the production of pro-fibrotic proteins suggests that they may be a poor choice for MD treatment.


One participant asked about the causative mechanisms for the fibrotic response of satellite cells. Dr. Partridge noted that this response happens equally on normal and abnormal muscle tissues, although there is an additional fibrotic response in dystrophic muscle. Collagen inhibits differentiation of these cells, and they lose their myogenicity in culture and with age.