Stem-cell therapy is valued for its potential to restore damaged or degenerating tissues. Stem cells are now regularly used to renew blood, and it looks as if the next success could be in treating dystrophic muscle.
The potential of stem-cell technologies to revolutionize medical care is causing great excitement among biologists and the general public. Recent studies on embryonic and adult stem cells, coupled with advances in our understanding of how they can be coaxed into forming particular cell types and tissues, have improved the prospects for addressing a host of untreatable diseases. Bone-marrow transplants to renew blood stem cells are now routine, but significant technological hurdles must still be overcome before the power of stem cells can be harnessed to regenerate solid organs such as muscle. On page 574 of this issue, Giulio Cossu and colleagues (Sampaolesi et al.)1 describe evidence from an animal model that a fairly straightforward infusion of stem cells into the bloodstream might one day be able to treat muscular dystrophyFootnote 1.
Cossu and colleagues focused on Duchenne muscular dystrophy, one of the most common and devastating inherited disorders, which is caused by mutations in the gene that encodes the dystrophin protein. A treatment for this condition has long been sought2, and a flurry of breakthroughs has led to current or planned clinical trials of at least five different treatment strategies3. Prominent among these are stem-cell transplantation and gene therapy, two approaches that can also be combined by manipulating an individual's own (autologous) stem cells to 'correct' the genetic defect before transplantation. Cossu and colleagues studied an animal model of Duchenne muscular dystrophy — the dystrophic GRMD dog — that closely mimics the human disease, in particular showing extensive muscle wasting and early death (unlike mouse models of the disease). They transplanted either donor stem cells or corrected autologous stem cells into the dogs and observed dramatic improvements in the animals' muscles.
A key factor in this work was the previous identification by the Cossu lab of a novel type of adult stem cell, termed a mesoangioblast, which can be harvested from small blood vessels4. Like all stem cells, mesoangioblasts can divide to make more of themselves, but they are also 'preprogrammed' to develop into muscle cells. Although a variety of stem-cell types can become muscle cells when injected into the bloodstream or directly into muscles5,6, mesoangioblasts show several distinct advantages over these other cells. They are relatively easy to isolate, and their numbers can be expanded greatly in tissue culture without losing the ability to form muscle. When mesoangioblasts are infused into arteries, they pass through vessel walls to engraft within, and rescue, damaged muscle cells with a surprisingly high efficiency7. Such properties are ideal for treating a disease such as muscular dystrophy in which muscles all over the body need to be repaired.
In the present study1, Cossu and colleagues isolated mesoangioblasts from normal and dystrophic dogs, expanded them in culture and infused them into a major hindlimb artery of the dystrophic dogs. Before infusion, the dystrophic mesoangioblasts were genetically 'corrected' by inserting copies of a gene that encodes a micro-dystrophin — a truncated form of the dystrophin protein — along with all the instructions needed to make the protein in muscle. These shortened dystrophins were used because they correct most dystrophic abnormalities in mouse models and can be transferred into stem cells far more efficiently than the full-length dystrophin8.
Infusion of either the normal or corrected dystrophic mesoangioblasts led to new expression of the dystrophin protein in a variety of different muscle groups in the dystrophic dogs. Dystrophin was also found in some muscles from the side of the dogs' bodies that had not been injected, indicating that mesoangioblasts could travel great distances before engrafting. To improve the efficiency of dystrophin production, the dogs were injected with cells up to five times at monthly intervals. In one animal, the cells were released from a catheter into the aorta — the vessel leaving the heart that supplies the body with blood. This therefore allowed more widespread dissemination of the mesoangioblasts. The results of the stem-cell infusions were dramatic: this last animal displayed a marked improvement in its dystrophy and was walking well 5 months after the final injection; the other animals recovered to a lesser degree. In general, dogs receiving donor cells improved more than those receiving corrected autologous mesoangioblasts. Some muscles in the injected dogs had nearly normal levels of dystrophin, and even the muscles with only moderate levels of dystrophin showed significantly improved structure and function (Fig. 1).
The different results obtained with normal and autologous mesoangioblasts have implications for their application in human patients. As with any transplant, unless the donor and recipient are immunologically matched, the recipient must be placed on lifelong immune suppression; this is not always effective and can have nasty side effects. The use of genetically corrected autologous stem cells would avoid this necessity, and so would be preferable if its effectiveness could be improved. There are at least two possible reasons for the reduced effectiveness of the autologous stem cells compared with the donor ones. First, micro-dystrophins are not fully functional, so alternative mini- or micro-dystrophins with improved functional activity9 might be more effective. Second, the micro-dystrophin used to correct the dystrophic mesoangioblasts was a human protein, and better results might have been obtained with dog dystrophin.
Cossu and colleagues' results1 provide compelling evidence that this method should be developed further for testing in patients. That will take several years, and may need many rounds of refinement in animals before any human trials can take place. Importantly, the corrected mesoangioblast approach could have widespread application to a variety of other muscle diseases besides Duchenne muscular dystrophy. The Cossu lab has shown that mesoangioblasts can improve muscle function in a mouse model of another type of muscular dystrophy10. There are more than 20 types of muscular dystrophy and numerous other muscle disorders, but treatment options are almost non-existent2,3. Perhaps these conditions will be among the first for which the promise of stem-cell technology for degenerative disorders can be realized.
This article and the paper concerned1 were published online on 15 November 2006.
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Nature Reviews Drug Discovery (2011)