Bone Marrow Generates New Neurons In Human Brains

"This study shows that some kind of cell in bone marrow, most likely a stem cell, has the capacity to enter the brain and form neurons," says Ẻva Mezey, M.D., Ph.D., from the National Institute of Neurological Disorders and Stroke (NINDS), who led the study.

Earlier work by Dr. Mezey and others has shown that bone marrow cells can enter the mouse brain and produce new neurons. However, the new study is the first to show that this phenomenon can occur in the human brain. The study was supported in part by the NINDS and appears in the January 20, 2003, online early edition of the Proceedings of the National Academy of Sciences.* The NINDS is a component of the National Institutes of Health, which is part of the U.S. Department of Health and Human Services.

In the study, Dr. Mezey and colleagues examined brain tissue taken at autopsy from four female patients – two adults and two children – who had received bone marrow transplants from male donors. The bone marrow transplants had been performed to treat leukemia and other non-neurological diseases, and the patients survived from 1 to 9 months after their transplants. The investigators searched the autopsied brain tissue for male cells, which contain a Y chromosome. The Y chromosomes in these cells served as a useful way of distinguishing donor-derived cells from those of the female transplant recipients. The researchers found cells with Y chromosomes in brain tissue from all four of the patients.

Most of the bone marrow-derived cells in the brain tissue were glia (support cells) and other non-neuronal cells. However, a small number of neurons from each brain also contained Y chromosomes, showing that those cells had developed from the transplanted male bone marrow. Most of these neurons were found in the cerebral cortex – the outer layer of the brain, which is responsible for conscious thought – and in the hippocampus, a region that helps with memory and other functions.

The Y chromosome-positive cells within each patient's brain appeared in clusters, rather than being randomly dispersed throughout the brain tissue. The clusters sometimes contained both neuronal and non-neuronal cells. This suggests that a single bone marrow-derived stem cell may migrate into an "area of need" within the brain and then change, or differentiate, into several other kinds of cells, Dr. Mezey says. The clusters also might result from a large number of marrow cells that are "called" to specific parts of the brain. Previous studies have suggested that stem cells can respond to signals from within the brain that guide them to damaged regions.

The brain sections with the largest number of marrow-derived neurons came from the youngest of the four patients, who had her transplant at 9 months of age. That patient also survived for 9 months after the transplant – much longer than the other patients in this study. The researchers do not know if the number of marrow-derived neurons in this patient was due to her young age or to the length of time she survived after receiving the transplant. The brains of young people usually undergo more changes than those of older people, and this might have encouraged the development of new neurons, Dr. Mezey notes. However, it is also possible that new cells enter the brain at a steady rate over time, regardless of a person's age.

It is possible that irradiation or other treatments that the four patients received might have increased the ability of marrow cells to enter the brain. However, other studies have suggested that bone marrow cells circulating in the blood enter the brain even in healthy subjects who have never received a bone marrow transplant, and there is no reason to think that a transplant is necessary for stem cells to enter the nervous system, Dr. Mezey says.

The numbers of marrow-derived neurons identified in the human brain tissue were very low – much lower than the numbers identified in a previous mouse study, says Dr. Mezey. However, the numbers might be greater in patients who survive for longer periods after transplant, she suggests.

Bone marrow contains at least two kinds of stem cells: hematopoietic stem cells, which usually differentiate into blood cells, and mesenchymal stem cells, which can differentiate into many kinds of cells in the body. The researchers do not yet know which type of cell differentiates into the neurons and other marrow-derived cells they identified in the brain.

Recent studies have shown that instead of developing into new cell types, adult stem cells sometimes fuse with mature cells from existing tissues that have already undergone differentiation. The resulting cells carry four sex chromosomes (X and Y chromosomes) instead of the usual two. While Dr. Mezey and her colleagues cannot exclude the possibility that fusion accounts for their results, they looked at several hundred donor-derived cells from one of the patients and did not see doubled sex chromosomes in any of the cells they examined.

Previous studies have found some cells with Y chromosomes in adult women who had not received any transplants. Researchers believe these Y cells may have come from a past pregnancy with a male fetus. However, two of the subjects in this study were children, and the male cells in those individuals could not have come from a pregnancy, says Dr. Mezey.

Scientists must now determine what growth factors or other signals prompt the bone marrow cells to enter the brain and develop into neurons. This may lead to new ways of treating Parkinson's disease or other disorders where neurons lost to disease are not normally replaced. Researchers might also be able to discover factors that can increase the number of cells entering the brain or prompt the cells to find useful targets.

"These studies are very much the beginning, but scientists should start to look down this road and find out if and how we can go further," says Dr. Mezey. She cautions that it is too early to know if this finding will lead to useful treatments for neurological disorders. She and her colleagues are now planning to study brain tissue from people who survived for longer periods after receiving a bone marrow transplant in order to see if the number of marrow-derived neurons increases with time. They also plan to study mice to determine which cells in the bone marrow develop into neurons.

The NINDS is the nation's primary supporter of biomedical research on the brain and nervous system.

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*Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. "Transplanted bone marrow generates new neurons in human brains." Proceedings of the National Academy of Sciences, Online Early Edition, January 20, 2003.