Scientists at the Massachusetts Institute of Technology (M.I.T.) report that they silenced symptoms of Parkinson's disease in rats using skin cells from an adult mouse that they reprogrammed to act like embryonic stem cells.
The M.I.T. group was one of three teams that last year created embryoniclike stem cells by introducing four genes into adult mouse skin cells. They then used the so-called induced pluripotent stem cells (IPS cells) to reverse a mouse version of the genetic disorder sickle-cell anemia, which causes normally circular red blood cells to form sickle-shaped, thereby impeding blood flow. The key is that embryonic stem cells are able to differentiate into other types of tissue in the body, whereas adult stem cells can only generate they type of tissue from which they hail.
Study co-author Marius Wernig, a postdoctoral biologist at M.I.T., reports in Proceedings of the National Academy of Sciences USA, that this is the first time scientists have successfully manipulated such cells to integrate into brain tissue and reverse damage caused by a neurodegenerative disease.
The team initially prepared the IPS cells in the lab and then injected them into the brain cavities of a developing mouse in the womb. Nine weeks after receiving the injections, long after the animal was born, the scientists examined its brain to see where the cells, which they'd labeled with a fluorescent marker, had gone. "They were all over the place and they were electrically integrated," says team leader Rudolf Jaenisch, a biology professor at M.I.T.'s Whitehead Institute for Biomedical Research and study co-author. "They looked like they were really functional cells."
Next, the group injected a toxin called 6-hydroxydopamine, which preferentially kills neurons that produce the neurotransmitter dopamine, into one side of the brains of adult rats. The solution was targeted to each animal's striatum, a brain region involved in motor control; it is the dopamine-producing nerve cells in this area that die during Parkinson's disease. As a result, the rats began having trouble balancing. "They rotate like hell" when they try to walk, Jaenisch says, because one side of their body has disrupted movement control.
After treating the IPS cells in a petri dish to set them on a path to mature into dopaminergic neurons, the cells were grafted into the dopamine-deficient hemispheres of the parkinsonian rats' brains. Four weeks after the transplant, the researchers noted less circling behavior in eight of nine treated rats. One even showed greater dopamine activity in the injured side of the brain than on the normal side, indicating, says Jaenisch, that "these IPS cells could be used also for generating function of dopaminergic neurons that could have therapeutic value."
But, Jaenisch notes, "there are many issues that need to be resolved" before the procedure can be adapted for use in humans. For one, scientists have yet to mimic the exact effects of Parkinson's in mice and rats, because the disease—which strikes an estimated 60,000 Americans per year—is so complex. But perhaps the biggest stumbling block is that the technique can also cause cancer. The reason: a carcinogenic gene is among those used to nudge adult skin cells to morph into embryoniclike stem cells. (The reprogramming process has been done without that gene but it yields far fewer IPS cells.) In addition, the retroviruses used to ferry the genes into the cells (where they copy their genes into cells they infect) may also be cancerous. Scientists are searching for a smaller molecule to replace them.