11/28/00
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EMBARGOED FOR RELEASE: Nov. 30, at 2 p.m. EST to coincide with publication in Dec. 1 issue of Science magazine.
"FROM BLOOD TO BRAIN"-DISCOVERY OF ADULT BONE MARROW CELLS IN BRAIN MAY LEAD TO NEW TREATMENT FOR PARKINSON'S AND TRAUMATIC BRAIN INJURY
STANFORD - Stanford researchers have shown for the first time that adult bone marrow cells can migrate to the brain, express neuronal-specific proteins and begin to look like their neuronal neighbors. The research, which will be published in the Dec. 1 issue of Science, suggests that an individual's own, genetically-modified bone marrow cells may someday be used to treat diseases like Parkinson's or Alzheimer's, or damage caused by a stroke or traumatic brain injury.
"We are really excited," said Helen Blau, PhD, professor and chair of the department of molecular pharmacology, of the work done in her lab. "You might expect this type of result with fetal cells, but with adult cells it's really amazing."
The use of adult cells bypasses some of the more intractable problems that come with using genetically engineered fetal cells: scarcity of material, potential rejection by the recipient and the need to deliver the cells directly into the brain.
Blau's reseach, initiated by graduate student Tim Brazelton, used bone marrow cells from adult mice whose cells had been engineered to express a protein that glows green (green fluorescent protein, or GFP). They injected the cells into the tail veins of normal mice whose bone marrow had been destroyed with radiation-a typical bone marrow transplant procedure. When the brains of the donor mice were analyzed two to six months later, the team saw green, bone marrow-derived cells throughout the central nervous system as well as in the bone marrow itself.
Most of the donor cells were found in the olfactory bulb, which undergoes a high rate of regeneration in rodents, perhaps due to their reliance on their sense of smell. But cells expressing GFP were also found in the hippocampus, cortical areas and cerebellum-areas responsible for a variety of functions, including learning and memory, conscious thought and emotion. Cell sorting showed that about 20 percent of the cells expressing GFP in the brain no longer expressed surface markers indicative of bone marrow cells, suggesting they had begun to assume a new role.
When the researchers microscopically examined individual donor cells in the olfactory bulb, they saw cells that were virtually indistinguishable from neighboring neurons. Additionally, bone marrow-derived cells in this area expressed proteins specific to neuronal cells.
"This is the first time that these cells have been found in the brain," said Blau, adding that previous research had identified bone marrow-derived cells that had become liver or muscle cells.
It's not known what calls these cells to the brain, Blau said. And the relative number of migrating cells is low: about 0.2 to 0.3 percent of the cells in the olfactory bulb expressed GFP. But the ability of the cells to migrate from the bone marrow to these areas and express neural proteins has exciting therapeutic possibilities.
"We're not poking holes in the brain; this is far less invasive," Blau said. "And we can genetically modify these cells to produce a product that would be useful for treating diseases like Parkinson's and Huntington's."
While Blau cautions that this research hasn't shown that the bone marrow-derived actually function as neurons, one experiment indicated the new cells are able to activate a common transcription pathway in concert with their neighbors. The result suggests that the cells are able to respond appropriately in their new environment, and raises the possibility that they may have other functional similarities to neuronal cells. Blau's team is working to increase the number of cells migrating to the brain in order to test their function and maximize therapeutic potential.
"Probably this migration is going on at a low rate all the time," said Blau. "But it's not enough to help fight degeneration from disease, or injury from stroke or trauma. We need to learn to enlist this ability."
To do that, it's necessary to understand the signals that beckon the bone marrow cells to the brain and tell them to express neuronal-specific proteins. Blau and her lab members would also like to determine whether only a specific subset of bone marrow cells are capable of responding to the call or if any bone marrow cell can assume neuron-like characteristics under the proper conditions.
"This research has opened up a lot of interesting research areas," Blau said. "What's badly needed in this field are ways to characterize these cells. Does damage attract them? Or do they respond to certain growth factors?"
Blau's interest in cell fate and differentiation is not new. In earlier work, she showed that nearly every normal adult cell tested, regardless of its previous function, was able to turn on muscle-cell-specific genes in response to appropriate stimuli. Her findings conflicted with the previously established belief that differentiation represented a dead end for cells, and raised questions about the role of local environmental signals in determining cell fate. Her current research re-emphasizes the plasticity of cell fate by showing that adult bone marrow cells have a remarkable ability to respond to their surroundings and suggests that their ability to migrate to different organs may someday be harnessed to provide new therapies for people suffering from neurodegenerative disease, stroke or other brain injury.
The results of Blau's research are appearing back-to-back in Science with a paper by Eva Mezey, MD/PhD, an investigator for the National Institute of Neurological Disorders and Stroke. Mezey used very different experimental techniques to track the movement of bone marrow-derived cells in mice and, like Blau, found the cells in the rodents' brains.
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