|Update (July 10, 2012) — This story was updated to reflect the availability of a podcast with MDA research grantee Emanuela Gussoni, who discusses the development of stem-cell-based treatments for muscular dystrophies.|
Using stem cells (a term that describes many kinds of cells) to repair degenerating muscles has been a goal of physicians and scientists for at least a decade.
Among the remaining challenges are:
In their experiments, many stem cell investigators have utilized mice that lack the dystrophin protein and show a disease resembling human Duchenne muscular dystrophy (DMD), largely because these mice are widely available and have been carefully studied. However, the principles learned from applying stem cell technology in one muscle disease may well have implications for other muscle diseases.
Several research groups have recently reported progress on the stem cell front.
Scientists at the University of Minnesota and the South San Francisco biopharmaceutical company iPierian have modified human embryonic stem cells and human induced pluripotent stem cells taken from healthy donors to coax them to become early-stage muscle cells.
The investigators accomplished this by inserting the gene for a protein called PAX7 into the cells and "turning on" PAX7 protein production at the appropriate time during cell development.
Not only did they obtain large quantities of cells destined to become muscle, but they also found that these cells integrated into the muscle tissue of dystrophin-deficient, DMD-like mice and improved the muscle strength of the animals. Some of the cells became specialized muscle repair cells known as satellite cells.
The transplanted cells were still present in the rodents' leg muscles 11 months after direct injection.
A caveat is that the mice in these experiments were not only dystrophin-deficient but also lacked functional immune systems, making it easier for them to tolerate the transplanted cells. Humans with normal immune systems might not readily tolerate stem cells transplanted from a donor.
In addition, the researchers injured the leg muscles of the mice with a toxin before injecting them, making them more receptive to integration with new stem cells than they might otherwise have been. Human muscles would not be injured in this way in a clinical trial.
To learn more, see the following:
Activation and proliferation of muscle stem cells known as satellite cells can be enhanced by a molecule called S1P, reports a research group supported in part by MDA.
The investigators (located at Children's Hospital Oakland Research Institute in California, the National Institutes of Health in Bethesda, Md., and Children's National Medical Center in Washington, D.C.) found that boosting S1P levels in the bloodstream improved muscle regeneration in DMD mice and might provide a new lead in the treatment of this disease.
Satellite cells are natural muscle repair cells located near mature muscle fibers. At one time, they were considered ideal candidates for transplantation, but that is no longer the case. Satellite cells appear to be a mixture of pre-muscle cells at different stages of development, and many of them, after being taken out and grown in laboratory dishes, lose their flexibility and repair capabilities.
The investigators on this new study found that dystrophin-deficient, DMD-like mice have low levels of the satellite-cell activator S1P, apparently because S1P is broken down quickly in these rodents.
When the investigators slowed the breakdown of S1P in the mice, they saw enhanced satellite-cell activation and markedly improved regeneration of damaged muscle fibers. (The muscle fibers of the DMD-like mice were abnormal because of dystrophin deficiency and also were injured by administration of a muscle toxin for purposes of the experiment.)
The researchers note that clinical trials using small molecules that slow the breakdown of S1P are under way in autoimmune disorders, and might be a feasible treatment strategy to investigate for DMD and possibly other muscle diseases.
To learn more, see:
A protein called MCAM can serve as a marker to distinguish between muscle side population (SP) cells that are likely to become muscle repair cells called satellite cells, and those that are likely to take other developmental paths, say investigators at Boston Children's Hospital who were funded in part by MDA.
SP cells were identified several years ago as a population of cells with muscle-generating potential, located in the spaces between muscle fibers. (In contrast, muscle satellite cells lie right next to each fiber.) It was found that some of the SP cells give rise to satellite cells, while others appear to develop into other cell types.
Identifying those that can become muscle and integrate into existing muscle tissue, following expansion (replication) in the laboratory, has been a continuing challenge.
The researchers on the current study found that, after expansion in the lab, the SP cells with the MCAM markers on their surfaces were significantly better at fusing together to form early-stage muscle fibers than were the other cell types they analyzed.
When they injected these MCAM-bearing SP cells directly into the leg muscles of dystrophin-deficient, DMD-like mice, they saw that some cells (but not many) integrated into the existing muscles of the animals. (These cells, however, integrated better than other cell types the researchers tried.)
The muscles of the host mice were damaged with a toxin to stimulate the regenerative process, and the mice were bred to lack functioning immune systems so that they would tolerate the human cells.
The investigators say the experiments show that MCAM appears to be a good candidate for the identification of cells that can replenish the satellite cell population, although their ability to integrate into existing tissue will need to be increased.
Caveats with these experiments are that the mice lacked functioning immune systems, making it easier for them to tolerate the new cells than it might be for humans with normal immune systems; the mouse muscles were damaged to induce regeneration, a strategy that would not be used in humans; and the ability of the cells to integrate into the mouse muscles was modest.
To learn more, see:
To learn more about stem cells in general, see the following: