Duchenne muscular dystrophy (DMD) is an inherited disease that affects about one in every 4,000 males born in the USA. It is caused by mutations in the DMD gene that lead to the protein dystrophin being either absent or faulty, which leads to muscle cell death, progressive muscle wasting and early death, with few patients surviving beyond their 40th birthday.
In recent years scientists have been investigating the possibility of transplanting healthy stem cells into the muscle of patients in order to replace the lost muscle cells and halt the progression of the disease, but it has proved difficult to identify muscle precursor cells that can both make new muscle cells and persist as a pool of precursor cells in the patient, the latter is an important consideration if repeated transplants are to be avoided since muscle cells wear out and need to be replaced. A paper published in this weeks issue of the scientific journal Cell by scientists at Harvard University is an important step towards developing a means to screen for the right cells and use them to treat DMD
In their work (1) Dr. Amy Wagers and her coworkers concentrated on a type of cell known as satellite cells that are closely associated with muscle fibers in mice and humans; by studying the proteins found on the surface of these cells they were able to identify a sub-population they termed skeletal-muscle precursor cells (SMPs) in mice that could produce muscle cells while maintaining a reserve of precursor cells for future rounds of muscle cell production. They next needed to evaluate these cells for their ability to do this when transplanted into an animal whose muscles were being damaged due to faulty dystrophin, in order to determine whether their ideas were correct.
They chose to use the mdx mouse model, a mouse which has a defect in the dystrophin gene and displays many of the biochemical and physiological characteristics of DMD. The mdx mouse displays less severe symptoms than humans with DMD, but like humans is characterized by progressive muscle wasting and early death and has been crucial to the development of many of the new therapies for DMD, including gene therapy and novel drugs, that are currently entering clinical trials. Dr. Wager’s work found that engraftment of transplanted SMPs into the muscles of mdx animals lead to the production of new muscle cells to replace lost to DMD, and that the transplants also showed therapeutic value by improving muscle histology and rescuing physiological muscle function i.e. the muscles got stronger. Analysis of the muscles of mice which received transplanted cells also showed that the second requirement that the transplanted cells should give rise to a pool of cells capable of acting as a source of muscle cells in future was also fulfilled.
This is very promising work, and marks an important milestone in the development of stem cell therapy for DMD. Before human trials can begin however more work will need to be done to develop methods of isolating and preparing human SMPs for use in clinical trials, and there remains the challenge of how to transplant the cells into all the muscles in the body where they are required.
1) Cerletti M. et al. “Highly Efficient, Functional Engraftment of Skeletal Muscle Stem Cells in Dystrophic Muscles” Cell Vol 134, Pages 37-47 ( 2008)