Stem Cells Restore Muscle in Muscular Dystrophy

Muscle stem cell transplant boosts diseased muscle function and replenishes stem cell pool Friday, 11 July 2008 Researchers at the Joslin Diabetes Center have demonstrated for the first time that transplanted muscle stem cells can both improve muscle function in animals with a form of muscular dystrophy and replenish the stem cell population for use in the repair of future muscle injuries. By injecting purified stem cells isolated from adult skeletal muscle, researchers have shown they can restore healthy muscle and improve muscle function in mice with a form of muscular dystrophy. Those muscle-building stem cells were derived from a larger pool of so-called satellite cells that normally associate with mature muscle fibers and play a role in muscle growth and repair. In addition to their contributions to mature muscle, the injected cells also replenished the pool of regenerative cells normally found in muscle. Those stem cells allowed the treated muscle to undergo subsequent rounds of injury repair, they found. "I'm very excited about this," said lead author Amy J. Wagers, Ph.D., Principal Investigator in the Joslin Section on Developmental and Stem Cell Biology, principal faculty member at the Harvard Stem Cell Institute and Assistant Professor of Stem Cell and Regenerative Biology at Harvard University. "This study indicates the presence of renewing muscle stem cells in adult skeletal muscle and demonstrates the potential benefit of stem cell therapy for the treatment of muscle degenerative diseases such as muscular dystrophy." "Our work shows proof-of-concept that purified muscle stem cells can be used in therapy," said Wagers, noting that in some cases the stem cells replaced more than 90 percent of the muscle fibers. Such an advance would require isolation of stem cells equivalent to those in the mouse from human muscle, something Wagers said her team is now working on. The study was designed to test the concept that skeletal muscle precursor cells could function as adult stem cells and that transplantation of these cells could both repair muscle tissue and regenerate the stem cell pool in a model of Duchenne muscular dystrophy, she said. Duchenne muscular dystrophy is the most common form of the disease and is characterized by rapidly progressing muscle degeneration. The disease is caused by a genetic mutation and there is currently no cure. The data from this new study demonstrate that regenerative muscle stem cells can be distinguished from other cells in the muscle by unique protein markers present on their surfaces. The authors used these markers to select stem cells from normal adult muscle and transferred the cells to diseased muscle of mice carrying a mutation in the same gene affected in human Duchenne muscular dystrophy. Satellite cells were first described decades ago and have since generally been considered as a homogeneous group, Wagers said. While anatomically they look similar under a microscope, they nonetheless show considerable variation in their physiology and function. In a previous study, Wagers' identified a set of five markers that characterize the only subset of satellite cells responsible for forming muscle, which they also refer to as skeletal muscle precursors or SMPs. In the new study, the researchers analyzed the stem cell and regenerative properties of those SMPs. When engrafted into muscle of mice lacking dystrophin, purified SMPs contributed to up to 94 percent of muscle fibers, restoring dystrophin expression and significantly improving muscle structure and contractile function, they report. (The dystrophin gene encodes a protein important for muscle integrity. Mice lacking dystrophin, also known as mdx mice, are a model for Duchenne muscular dystrophy, the most prevalent form of muscular dystrophy.) "Importantly, high-level engraftment of transplanted SMPs in mdx animals shows therapeutic value — restoring defective dystrophin gene expression, improving muscle histology, and rescuing physiological muscle function," the researchers said. "Moreover, in addition to generating mature muscle fibers, transplanted SMPs also re-seed the satellite cell niche and are maintained there such that they can be recruited to participate in future rounds of muscle regeneration.” "Taken together, these data indicate that SMPs act as renewable, transplantable stem cells for adult skeletal muscle. The level of myofiber reconstitution achieved by these myogenic stem cells exceeds that reported for most other myogenic cell populations and leads to a striking improvement of muscle contraction function in SMP-treated muscles. These data thus provide direct evidence that prospectively isolatable, lineage-specific skeletal muscle stem cells provide a robust source of muscle replacement cells and a viable therapeutic option for the treatment of muscle degenerative disorders." Wagers noted however that there may be complications in the delivery of cell therapy in humans, particularly for those with conditions influencing skeletal muscle throughout the body. Even so, the new findings present an "opportunity to understand what happens [to these regenerative cells] in disease and identify factors and pathways that may boost their activity," she said. "We may get a handle on drugs that could target muscle impairment" not only in those with muscular dystrophies, but also in elderly people suffering from the muscle wasting that comes with age. "Once the healthy stem cells were transplanted into the muscles of the mice with muscular dystrophy, they generated cells that incorporated into the diseased muscle and substantially improved the ability of the treated muscles to contract," said Wagers. "At the same time, the transplantation of the healthy stem cells replenished the formerly diseased stem cell pool, providing a reservoir of healthy stem cells that could be re-activated to repair the muscle again during a second injury." According to the paper, these cells provide an effective source of immediately available muscle regenerative cells as well as a reserve pool that can maintain muscle regenerative activity in response to future challenges. "This work demonstrates, in concept, that stem cell therapy could be beneficial for degenerative muscle diseases," Wagers said. Wagers also said the study will lead to other studies in the near-term that will identify pathways that regulate these muscle stem cells in order to figure out ways to boost the normal regenerative potential of these cells. These could include drug therapies or genomic approaches, she said. In the long-term, the idea will be to replicate these findings in humans. "This is still very basic science, but I think we're going to be able to move forward in a lot of directions. It opens up many exciting avenues," she said. The Wagers Lab at Joslin studies both hematopoietic stem cells, which constantly maintain and can fully regenerate the entire blood system, as well as skeletal muscle stem cells, involved in skeletal muscle growth and repair. The work is aimed particularly at defining novel mechanisms that regulate the migration, expansion, and regenerative potential of these two distinct adult stem cells. About Joslin Diabetes Center Joslin Diabetes Center is the world's largest diabetes clinic, diabetes research center and provider of diabetes education. Joslin is dedicated to ensuring people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure for the disease. Founded in 1898 by Elliott P. Joslin, M.D., Joslin is an independent non-profit institution affiliated with Harvard Medical School. Reference: Highly Efficient, Functional Engraftment of Skeletal Muscle Stem Cells in Dystrophic Muscles Massimiliano Cerletti, Sara Jurga, Carol A. Witczak, Michael F. Hirshman, Jennifer L. Shadrach, Laurie J. Goodyear, and Amy J. Wagers Cell, Vol 134, 37-47, 11 July 2008 ......... ZenMaster

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