Cultured Neural Stem Cells Reduce Symptoms In Model Of Parkinson's Disease

July 20, 1998

For decades, researchers have imagined treating human diseases by replacing damaged cells with stem cells -- embryonic cells from which all other kinds of cells develop. While the potential benefits are enormous, such strategies have been limited by an uncertain supply of stem cells. Now, scientists have shown that neural stem cells can be multiplied and raised to maturity in the laboratory and that these cells can greatly reduce symptoms in an animal model of Parkinson's disease.

The study is the first to show that neural stem cells grown outside the body can form specific kinds of neurons -- in this case, dopamine-producing cells -- and that these neurons can survive and function normally when they are transplanted into the living brain. Dopamine is an important nerve signaling chemical, or neurotransmitter, and the loss of dopamine-producing cells in one region of the brain is responsible for the symptoms seen in Parkinson's disease. The new finding suggests that cells multiplied in culture may ultimately prove useful in treating Parkinson's and other nervous system diseases. It also provides new opportunities for studying how the brain develops that may greatly improve understanding of nervous system disorders, says Ronald McKay, Ph.D., of the National Institute of Neurological Disorders and Stroke (NINDS), senior author of the report which will appear in the August 1998 issue of Nature Neuroscience (1).

"Cells are the ultimate device for delivering substances to the brain, so this could become one of the most widely used therapies in medical research," says Dr. McKay.

Unlike the original cells of the embryo, which can form literally any kind of cell, neural stem cells are restricted to becoming nervous system cells. However, they still can develop into all the types of cells that make up the brain and spinal cord. The process in which cells that start out with unlimited potential fates develop into specific types of mature, non-dividing cells is called differentiation.

In the new study, Dr. McKay and his colleagues Lorenz Studer, M.D., and Viviane Tabar, M.D., took neural stem cells from the brains of rat embryos and grew them in culture dishes with a protein called basic fibroblast growth factor that helps the cells survive and divide. After the cells multiplied for 6 to 8 days, the growth factor was removed and the cells were allowed to aggregate into free-floating spheres of neurons. The neurons in the spheres began to develop functioning connections with each other, producing dopamine as well as several other kinds of neurotransmitters. When the spheres were injected into the brains of rats that were missing the dopamine-producing region on one side of their brains, the rats' Parkinsonian symptoms gradually diminished. Most showed about a 75 percent improvement in motor function 80 days after they received the transplants.

At present, the cells can be multiplied only 10 to 100 times, not enough to provide a good supply of stem cells for routine use in the clinic. "We've opened a door, but it's not yet clear that you can drive a truck through it," says Dr. McKay. However, he believes it may soon become possible to expand stem cells as many as 10,000 times. If so, thousands of patients might ultimately be treated with cells derived from one source. This enhanced supply of cells would make clinical trials much more feasible while reducing the ethical concerns associated with use of embryonic tissue. The ability to grow neural stem cells in the laboratory also provides an excellent opportunity for genetically manipulating the cells to improve their chances of surviving and connecting to the rest of the brain after transplantation. For example, scientists might be able to manipulate neural stem cells so that they produce not only dopamine, but also growth factors that enhance cell survival and integration.

If all goes well, cultured neural stem cells could be applied in human clinical trials in the next 2 to 3 years, Dr. McKay says. The biggest obstacle to this type of therapy now may be controlling what the cells do once they are injected, he adds. For example, they might die, grow the wrong connections, or even form tumors if conditions are not exactly right.

Several groups of clinical investigators are already studying whether human embryonic dopamine-producing cells can effectively treat Parkinson's disease. More than 200 patients have received transplants of these cells. However, the potential for this type of therapy to become widely available has always been limited by difficulty in obtaining embryonic tissue. The new study shows that it now may be possible for researchers to grow their own easily controlled supply of stem cells.

While the new procedure has great promise for improving treatment of neurological disorders, it also will be important in helping researchers understand how the brain develops. The neural stem cells in this experiment went through all the basic steps of brain development outside of the body -- they multiplied, differentiated, and formed functioning connections with other cells. By manipulating cells in culture during these crucial stages, researchers could study how complex brain structures are built, damaged, and rebuilt, allowing them to thoroughly test many theories about how these processes occur. Culturing stem cells also will allow researchers to test different strategies for enhancing production of specific kinds of cells and improving how those cells integrate with the brain once they are transplanted. For example, the cultured cells could be temporarily arrested in their development so that they are "primed" for integration when they are transplanted into the brain.

The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.

(1) Studer, L.; Tabar, V.; and McKay, R.D.G. "Transplantation of expanded mesencephalic precursors leads to recovery in Parkinsonian rats." Nature Neuroscience, Vol. 1, No. 4, August 1998, pages 290-295.

This release will be posted on EurekAlert! at http://www.eurekalert.org and on the NINDS home page at http://www.ninds.nih.gov/whtnwhp.htm.
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NIH/National Institute of Neurological Disorders and Stroke

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