radbod darabi/utsouthwesternCell integrated into the muscle produces dystrophin (red)radbod darabi/utsouthwestern
Recent research results bring new hope to people who suffer from Duchenne muscular dystrophy, a terminal degenerative disease that causes progressive loss of muscular strength from childhood. Brazilian biochemist Rita Perlingeiro, working at the Southeast Medical Center at the University of Texas, in the US, was able to produce muscle cells from the embryo stem cells of mice and incorporate them into the muscles of animals with the genetic mutation that causes the disease. The results were published in the January edition of Nature Medicine magazine.
Embryo stem cells have the ability to produce any type of body tissue. However, according to Rita, in a culture medium they produce few muscle cells. “The environment is not appropriate, it lacks the control factors that lead to the production of this type of tissue in the embryo,” she adds. Therefore stem cells require a stimulus to become muscle cells. Rita was able to achieve this using the antibiotic doxycycline, which activates the PAX3 gene. “In congresses it had already been stated that this gene induces the production of muscle cells. She was the first person to show it,” states Mayana Zatz, from the Human Genome Studies Center at the University of São Paulo. “However, it is still a long way from clinical use,” she states.
The most common model used in dystrophy research studies are genetically modified mice that do not produce dystrophin protein, whose absence causes impaired muscle functions, a characteristic of the disease. But when researchers inject the modified stem cells in these rodents to produce dystrophin, tumors often result. According to Rita this occurrs because not every stem cell receives the stimulus to turn into muscle cells and there were some non-specialized cells in the culture medium. “Having just a few undifferentiated cells is enough to cause tumors,” explains the biochemist.
Therefore, Rita developed a way to recognize muscle cells and extract them from the culture medium. The next step was to inject these cells, marked with a green protein that makes it easy to locate them in the mouse’s bloodstream. Even Rita was surprised with the result: “Even when they are injected into a vein, rather than directly into the impaired muscles, the cells only fasten on to the muscles, and not to other tissue.” Up to the fourth month after treatment, no tumors appeared.
Even better. The cells are working as muscle cells: producing dystrophin and improving muscular strength. A limitation of the study is that modified mice may only be considered as partial models in the Duchenne dystrophy study. Unlike humans, these rodents do not lose mobility with dystrophin deficiency. “One is unable to tell the difference between sick and normal mice just by looking,” states Rita. To check if the cells that were incorporated into the muscles were in fact functioning as muscle cells, Rita used a device to measure the muscle contraction capacity – with dystrophin deficiency, muscles lack normal tone. “The treated animals didn’t perform like the healthy ones, but they improved significantly relative to the specimens that didn’t get the transplant,” she states.
There is still much work to be done before this achievement reaches clinical use: comprehensive tests must be carried out to guarantee that cells are only incorporated into the damaged muscle; researchers must check whether once they are absorbed into the muscle, they multiply and create functional musculature; testing the technique in dogs, an important model for the study of muscular dystrophy, as they have similar symptoms to humans; and obtaining the same effect with human embryo stem cells. And lastly, if feasible, using new adult stem cell manipulation techniques to avoid the ethical problems related to the use of embryos. It is a long road ahead but there is no shortage of stamina to tackle it.
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