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Can bone marrow seed the brain with new neurons?

http://www.neurologyreviews.com/mar03/mar03_bonemarrow.html

March, 2003
Volume 11, No. 3
C. Justin Romano
Neurology Reviews

New research suggests that stem cells from bone marrow transplants can enter the human brain and generate new neurons, as well as glial and endothelial cells. The phenomenon had previously been reported in rodents, but the work by Eva Mezey, MD, PhD, of the National Institute of Neurological Disorders and Stroke, and colleagues is the first to demonstrate such behavior in humans. “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,” Dr. Mezey said. The finding may open a door to new treatments for stroke, Parkinson’s disease, and other neurologic disorders.

FROM AUTOPSY TO EUREKA!

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 to treat leukemia and other nonneurologic disorders. Patients survived from one to nine months after the transplants.

Using immunocytochemistry and fluorescent in situ hybridization histochemistry, the investigators examined the brain tissue for Y chromosome–positive cells and found them in several brain regions. “Most of [the cells] were nonneuronal (endothelial cells and cells in the white matter), but neurons were certainly labeled, especially in the hippocampus and cerebral cortex,” they reported in the February 4 Proceedings of the National Academy of Sciences.

While the researchers cannot discount the possibility that cellular fusion accounted for their findings, Dr. Mezey said that their examination of hundreds of donor-derived cells from one of the four patients did not reveal any evidence of the doubled sex chromosomes characteristic of fused cells. Likewise, the fact that two of their subjects were children eliminated the possibility that the Y-positive cells may have come from a past pregnancy with a male fetus, she added.

A FEW NEW NEURONS

The Y chromosome–positive cells appeared in clusters that sometimes contained both neuronal and nonneuronal cells, including a mixture of oligodendrocytes, astrocytes, and possibly microglia, as well as endothelial, meningeal, and ependymal cells. Neuronal cells were “consistently in the minority,” Dr. Mezey noted. The researchers found two to five Y-positive neurons per 10,000 human neurons. Comparatively, prior research had found as many as 50 Y-positive neurons per 10,000 in rodents, though whether this was a species-related discrepancy or due to the very short survival times after transplant remains unknown.

Still, the researchers had some hope that the numbers of such cells in humans might increase over time. The highest concentration of labeled neurons (seven per 10,000) was found in tissue from a 9-month-old patient who was the youngest studied and who also had the longest posttransplant survival time (nine months). The increase might be due to either of those factors, Dr. Mezey commented. She allowed that it is also possible that neurons enter the brain at a steady rate over time, regardless of age.

CLUSTERS OF HOPE

The clustered nature of the Y-positive cells in their findings suggested to Dr. Mezey that the distribution of these cells in the brain is not random. “Nondifferentiated cells may enter an area and then further propagate there,” she said. It is possible that “one undifferentiated cell migrates into an ‘area of need’ and then goes through asymmetrical divisions to produce different lineages of cells.” Dr. Mezey also speculated that areas in need of new cells might be able to “signal potential stem cells to coax them into the region, and then clonal expansion occurs to help restore the number of cells to normal.”

Finding those factors that mitigate the migration of stem cells to lesioned or injured areas of the brain will be very important in the quest to use bone marrow to repair the brain. “These studies are very much the beginning,” Dr. Mezey said, cautioning that it is too early to truly ascertain whether these findings will prove useful in the treatment of neurologic diseases. “Scientists should start to look down this road and find out if and how we can go further.” Her group is planning to study brain tissue from patients who survived longer after bone marrow transplants to test the theory that the number of Y-positive neurons will increase over time. They also plan mouse studies to determine which cells in the marrow differentiate into neurons.

Suggested Reading

Mezey E, Chandross KJ. Bone marrow: a possible alternative source of cells in the adult nervous system. Eur J Pharmacol. 2000;405:297-302.

Mezey E, Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A. 2003;100:1364-1369.

Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61:364-370.

Verfaillie CM. Hematopoietic stem cells for transplantation. Nat Immunol. 2002;3:314-317.
 

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