UF scientists show adult blood stem cells can transform into brain cells in people

April 29, 2004

GAINESVILLE, Fla. — University of Florida scientists have discovered that male blood stem cells evolved into male brain cells in three women who underwent bone marrow transplantation to treat cancer.

The findings, reported in the May issue of The Lancet, will need to be confirmed in larger studies, but they help bolster the case that adult stem cells – like their embryonic brethren – can actually morph into other cell types, not simply appear to do so by fusing with them. If the results hold up, scientists might someday find ways to use bone marrow transplantation, essentially a rich source of adult blood stem cells, as the basis for new treatments aimed at correcting an array of brain disorders.

“What this suggests is that the bone marrow may play a normal role in repairing your brain, and if that’s the case we may be able to discover ways of making it do a better job and help to repair some neurological disorders,” said study senior author Edward Scott, director of the Program in Stem Cell Biology and Regenerative Medicine at UF’s Health Science Center and an associate professor of molecular genetics and microbiology at the UF Shands Cancer Center. “And it raises the question: For certain types of neurological disorders, would some sort of bone marrow transplant be an appropriate therapy? This could be a new avenue to look at new ways of trying to repair neurologic disease.”

Researchers made the discovery after studying brain tissue samples taken from three women who died in the months or years after they received a bone marrow transplant to treat leukemia. All had received infusions of marrow donated by their brothers. Scientists were able to isolate nearly 10,000 brain cells of various types, and discovered a small percentage of them harbored a Y male chromosome, instead of the usual X chromosomes characteristic of women.

That meant the male blood stem cells found in the transplanted bone marrow had somehow converted into brain cells. Scientists think this might have occurred because the chemotherapy or radiation the women received to fight their cancer also damaged some brain cells. The body sought to fix itself by cueing a repair mechanism that urged blood stem cells to cross the blood-brain barrier and migrate to injured sites, where they transformed.

“This backs up what’s been seen in animal models,” Scott said. “Now we’re trying to see how frequent this truly is, how well it works. Was there something special about the way these patients were transplanted? That’s what the larger study we plan to do will be able to tell us. We in the field need to do a lot more work to see if the findings are real and useful or just an interesting observation.”

Scott, the study’s principal investigator, collaborated with UF postdoctoral fellow Dr. Christopher Cogle, the paper’s lead author, and with other UF faculty, including Dr. John Wingard, director of the Bone Marrow Transplant Program at Shands at UF, and Dennis Steindler, a professor of neuroscience and neurosurgery at UF’s McKnight Brain Institute. The studied was funded by the National Institutes of Health and Shands at UF.

The tissue samples were taken during autopsies from a region of the brain called the hippocampus, known to be a site where brain cells actively regenerate. Scientists identified three cell types, neurons, astrocytes and microglia. The “transgender” cells accounted for 1 percent to 3 percent of the total number of cells they sampled.

“Neurons and astrocytes are the parts of the brain that help make and guide connections and conduct the thought process,” Scott said. “The microglia are essentially thought of as the garbage men of the brain. They go around and take care of dead cells and unwanted material. And there’s a possibility the microglia come from different areas of the body. For a long time now, people thought the microglia probably originated in the bone marrow. There’s actually some decent evidence for that and our research also helps show that’s the case. The question is, how related are all these things?”

All patients had microglia traced back to the transplanted blood stem cells. But only one patient also had neurons and astrocytes that evolved from blood stem cells; of those studied she was the furthest from transplantation, about six years out. The others died within three to nine weeks of receiving their transplants.

Researchers said the development of neurons and astrocytes may simply occur much more slowly, over years. In addition, they said the phenomena could not have resulted from cell transfer between mothers and sons, a situation known as microchimerism. Microchimerism occurs when cells shift from a fetus to the mother during pregnancy, and remain in her circulation in low but detectable levels for decades. However, none of the three women had given birth to boys.

The findings add to the ongoing academic debate about whether stem cells can truly transform into new cell types, or whether they simply fuse with other cells and take on the appearance of having evolved into them.

“We were very surprised by these results, to be honest,” Cogle said. “We took many steps to confirm what we found. One of the experiments questioned whether the phenomenon is due to fusion of a male blood cell and a female brain cell. To do this we looked for brain cells that had extra X chromosomes. Whereas male cells usually have one X chromosome and one Y chromosome, a fused cell would have XXY or XXXY chromosomes. In fact, we found no male brain cells with extra X chromosomes.

“The second thing we did was to look at the tissues, sectioned in serial fashion so we could track one neural cell from beginning to end, to ask the question ‘Is there more than one X chromosome?’” he added. “Again, we found no cells that had extra X chromosomes, indicating no evidence for fusion.”

Studies elsewhere have shown that some types of neurons can derive from fusion of circulating blood cells with original neurons in the brain, said Dr. Neil Theise, a stem cell biologist and clinical pathologist at Beth Israel Medical Center in New York, adding, “This paper unambiguously shows that some neurons can arise not by fusion but by transdifferentiating and confirms that both mechanisms are ways in which adult blood stem cells can engraft in nonblood organs. The importance of that is people have used the fusion issue to undercut the importance of what adult stem cells can do, to even question whether they can do anything special, and by restoring balance to the field, this paper helps to re-establish the potential utility of adult stem cells.”