When researchers announced two years ago that they had found a way to turn ordinary skin cells into stem cells, it opened up the possibility that stem cell therapies might sidestep the logistical and ethical hurdles of obtaining stem cells from embryos. These “reprogrammed” stem cells seem to have the ability to transform into any kind of cell, a property known as pluripotency. But the concept has also met with skepticism about the abilities and potential dangers of the cells. A new study in the Proceedings of the National Academy of Sciences by scientists at MIT and Harvard shows that reprogrammed cells, also called induced pluripotent stem (iPS) cells, can become functioning neurons when transplanted into the brains of mice and rats; the researchers also showed that the cells can improve symptoms in a rat model of Parkinson’s disease.
The research team, led by Rudolph Jaenisch at the Whitehead Institute for Biomedical Research at MIT, used the previously developed method for reprogramming cells, in which skin cells of a mouse can be made pluripotent when infected with a retrovirus carrying four genes. First, the scientists showed that they could turn mouse skin cells into functioning neurons in culture. They then transplanted these neurons into the brains of mice while they were still fetuses. After the mice grew into early adulthood, the researchers examined the brains and identified the transplanted cells, which had been labeled with a fluorescent marker. The cells “migrate nicely into the brain and mature in the brain,” says Marius Wernig, a postdoctoral fellow at the Whitehead Institute. “They adopt functions of mature neurons.”
Next, the group tested whether these functioning neurons could repair a defect in an animal model of disease. Parkinson’s involves a loss of a specific population of neurons—-those that produce dopamine. The study used a model for Parkinson’s in which rats are given a toxin that kills dopamine neurons on one side of the brain. Although the animals appear normal, when their dopamine neurons are stimulated with amphetamine, they begin to turn in circles in the direction of the damaged side. In rats that were given transplants of neurons derived from iPS cells, the motor defect improved.
John Gearhart, a stem cell biologist at Johns Hopkins School of Medicine who was not involved in the study, says that previous studies with the reprogrammed cells have had conflicting results–some studies show that the cells have similar abilities as embryonic stem cells, while others don’t. “This is an important study,” says Gearhart, because it compares the iPS cells with neurons derived from embryonic stem cells.
It is not known exactly how boosting the expression of just four genes manages to induce such a powerful state. Two of the genes are known oncogenes, or tumor promoters, that help cells proliferate; the other two are involved in maintaining the pluripotency of stem cells. Although the study provides a proof of concept, much has to be done before the reprogrammed stem cells could be used in the clinic. At present, they are considered unsafe for use in humans because the way they are engineered has the potential to cause cancer. Wernig says that the next major effort is “to try to reprogram human cells without the use of a retrovirus and without oncogenes,” perhaps by targeting the genes with drugs.
For many years, a small group of patients with Parkinson’s disease have received experimental cell transplants using dopamine neurons derived from fetuses. But the use of fetal tissue poses ethical and logistical hurdles for widespread use. Scientists have performed similar experiments in animals using stem cells derived from embryos or created with nuclear transfer, also known as therapeutic cloning. But iPS cells offer a way to avoid the use of embryos as well as the technical challenges of nuclear transfer. And if the cells came from a patient’s own skin, there would be no potential complications from immune rejection of foreign tissue.
When the team first performed the experiment, many rats developed tumors, which seemed to arise from the fact that not all of the iPS cells had fully transformed into neurons when they were transplanted. Tumors such as these have also been observed in experiments with embryonic stem cells. In this study, however, the researchers performed another set of transplants, first using a cell-sorting method that can identify and remove any cells that have failed to differentiate. “When we eliminated the undifferentiated cells from mixture, we got very clean transplants,” says Ole Isacson, a neurologist at Harvard Medical School who collaborated on the transplant experiments. The rats given these purified cells did not go on to develop tumors. He believes that the varying purity of transplants may prove to be a key factor in why some of the fetal cell transplants have not succeeded as well as others.