June 11, 2009 – A discovery that strengthens the body’s ability to repair muscle tissue could lead to new treatments for people with muscular dystrophy and other degenerative muscle diseases.

“This discovery shows us that by targeting stem cells to boost their numbers, we can improve the body’s ability to repair muscle tissue,” said Michael Rudnicki, scientific director of Canada’s Stem Cell Network, whose research was funded by the  Muscular Dystrophy Association (MDA).

The research shows that a protein called Wnt7a increases production of adult stem cells in muscle tissue, building tissue that leads to bigger, stronger muscles.  Rudnicki’s team introduced Wnt7a into mouse muscle tissue, increasing the population of satellite stem cells that fueled the muscle-building process. Researchers discovered that muscle tissue mass increased by almost 20 percent.

“This finding firmly identifies Wnt7a as a target for drug development for muscle disease,” said Sharon Hesterlee, SVP and Executive Director of MDA Venture Philanthropy. “The more we understand the ways in which muscle normally repairs itself, the more therapeutic options we will have.”

The stem cell-based therapies of regenerative medicine continue to offer increasing evidence for the successful treatment of a variety of diseases such as Muscular Dystrophy. In fact, stem cell therapy has already shown very positive results in reversing the effects of Muscular Dystrophy in animal models.

Stem cells replace the missing proteins, such as dystrophin in Duchenne and Becker MD, merosin in Congenital MD, emerin in Emery-Dreifuss MD, adhalin and the four sarcoglycans that constitute the dystrophin-glycoprotein complex in Limb-Girdle MD, dysferlin in Distal MD, and stem cells may also correct the abnormally long repetition of the DNA sequence from the myotonin protein kinase enzyme gene that is found in Myotonic MD.

Replacing such proteins that are either absent or defective results not only in the regeneration of damaged tissue but also in the protection of muscle fiber from further degeneration.

As already described, muscle tissue exhibits a natural regenerative capacity in healthy individuals. This innate, characteristic feature of muscle fiber makes muscle-related diseases such as the muscular dystrophies prime candidates for stem cell therapy. In fact, since stem cells are naturally present within muscles, one approach is to stimulate those stem cells that already exist within the muscle fibers. Even when stem cells from an external source are used, the muscle cells of the body are highly responsive to such stimuli, with a natural tendency to regenerate themselves, and in fact such properties are prime hallmarks that distinguish muscle tissue from most other tissue in the body. While basic catabolic (breaking down) and anabolic (building up) processes occur in all tissue types throughout the body, at all times, such fundamental properties of metabolism are most actively “programmed” into muscle tissue.

Muscle fibers contain a highly specialized type of cellular environment that naturally promotes the continuous regenerative capacity of this tissue. Such a cellular milieu consists of a number of built-in mechanisms and “cues” that automatically trigger regeneration whenever fibers are worn down or injured. More so than any other types of tissue throughout the body, muscle tissue is constantly being worn down and rebuilt, even under normal circumstances in healthy individuals, and it is part of the very nature of muscle that it cannot be built up unless it is first torn down. Such natural processes are of increasing interest to researchers, and a number of national and government organizations, such as NIAMS, have funded various studies that are directed toward understanding these molecular and cellular processes. Stem cells are therefore particularly effective in such a natural cellular environment that is already highly conducive to regeneration.

Stem cells may also be used as a delivery system for functional genes, such as the dystrophin and other genes, to replace the defective genes in MD patients. In fact, such corrective gene replacement therapy with stem cells has already been successfully performed with dystrophic mice.

A family of natural growth-stimulating proteins known as “Wnt” has been found to prompt stem cells to rebuild damaged muscles in mouse models. The Wnt family of proteins constitute a group of signaling molecules that are known to regulate cell-to-cell interactions during embryogenesis and cancer, but given the right cellular signals and “cues”, the Wnt proteins have also been shown to stimulate stem cells that naturally exist within the muscle tissue, thereby regenerating muscle fiber after an injury. Wnt itself is naturally present in cells throughout life and becomes activated whenever needed.

Stem cells known as mesoangioblasts have shown the ability to cross the inner lining of blood vessels and migrate extensively throughout tissue in the regeneration of muscle. Mesoangioblasts may be collected from a person’s blood vessels, genetically “fixed” in the laboratory where they are allowed to multiply, and then injected back into the bloodstream of the patient where they migrate to the muscles and begin the process of regenerating cells. Such a procedure represents autologous transplantation (in which the donor of the stem cells is the same person as the recipient), in which immune rejection does not occur. This process has been successfully demonstrated in various animal models.

One such example involved the Stem Cell Research Institute in Milan, Italy, who directed a study in which mesoangioblasts were used to treat MD in a mouse model. The mice showed measurable improvement in their musculature as a result of receiving the stem cells. The findings were published in the journal Science.

Another example involved scientists in Italy and France who collaborated on a study in which dogs with Duchenne MD were treated with autologous mesoangioblasts and consequently experienced a regeneration of dystrophin as well as a regeneration of some of their muscle strength. Results of the study, which was conducted in 2006 and led by Dr. Maurilio Sampaolesi, were published in the journal Nature.

Similarly, researchers at the Children’s Hospital in Boston conducted a study with autologous stem cells that were derived from bone marrow and transplanted into mice which were bred to be deficient in dystrophin. The stem cells were found to differentiate into a variety of cell types including muscle cells, with 10% of the muscle fibers expressing dystrophin within 12 weeks after the mice were injected with the bone marrow stem cells.

John Huard, Ph.D., and colleagues at the Children’s Hospital of Pittsburgh, in collaboration with the University of Bonn in Germany, conducted a study in which they isolated a subpopulation of muscle stem cells which were then administered to mice that had been bred to express symptoms of MD. The stem cells were shown specifically to replace dystrophin in the mice, resulting in measurable improvement in the musculature of the mice. The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the Muscular Dystrophy Association, the Parent Project Muscular Dystrophy Research and the Children’s Hospital of Pittsburgh.

Additionally, muscle-derived stem cells (MDSCs) have been isolated and cloned from postnatal muscle and have been shown to differentiate into muscle tissue and other cell lineages. A NIAMS-supported laboratory has developed a method for isolating MDSCs from young mice and expanding these colonies of cells for more than 200 doublings, during which time the cells retained their ability to synthesize muscle-specific proteins and to develop muscle cell morphology, both in culture and when transplanted back into the mouse muscle tissue. Such a high level of cultural expansion had previously been attributed exclusively to embryonic stem cells, but such properties have now been widely replicated with multiple types of adult stem cells including bone marrow-derived and muscle-derived stem cells.

Adult stem cells offer the same pluripotency of embryonic stem cells, but without the danger of forming teratomas (tumors), which remains a serious risk from embryonic stem cells. It is neither necessary nor desirable to use embryonic stem cells in the treatment of Muscular Dystrophy or other diseases, since a growing number of studies are showing increasing success with adult stem cells. In fact, the only stem cell studies that have ever shown success in the treatment of any human disease have involved adult stem cells, since no study has ever been conducted in which a disease was successfully treated with human embryonic stem cells, although this fact is not generally reported by the media. Ethics and politics aside, adult stem cells are highly preferable to embryonic stem cells purely for scientific reasons. (Please see the section entitled “Stem Cell Primer” for an explanation of the different properties of the different types of stem cells).

The various muscular dystrophies constitute a tremendous burden, not only to the individuals afflicted with these diseases, but also to their families and indeed to national economies.

Adult stem cell therapy offers a safe and potentially effective treatment of a disease which previously has been considered irreversible.