Stanford Report, December 6, 2000
|Bone marrow cells in brain
give hope for stroke, Parkinson's treatment
BY KRISTA CONGER
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, published in the Dec. 1 issue of Science magazine, suggests that an individual's own, genetically modified bone marrow cells may someday be used to treat such diseases as Parkinson's and Alzheimer's as well as damage caused by stroke and traumatic brain injuries.
"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 research, initiated by graduate student Tim Brazelton, used adult mice whose bone marrow 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 mice were analyzed two to six months later, the team saw green, bone marrow-derived cells throughout the central nervous system and 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 the cells were also found in the hippocampus, cortical regions and cerebellum -- areas responsible for a variety of functions, including learning and memory, conscious thought and emotion. Cell sorting showed roughly 20 percent of the cells no longer expressed surface markers indicative of bone marrow cells, suggesting they had begun to assume a new role.
When researchers microscopically examined individual donor cells in the olfactory bulb, the cells 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 these cells have been found in the brain," said Blau, adding that previous research identified bone marrow-derived cells that became 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 the research hasn't shown bone marrow-derived cells actually function as neurons, one experiment indicated the new cells could activate a common transcription pathway in concert with their neighbors. The result suggests the cells are able to respond appropriately in their new environment, and raises the possibility they may have other functional similarities to neuronal cells. Blau's team is working to increase the number of cells migrating to the brain 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 beckoning bone marrow cells to the brain and telling 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 is 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 said the finding required a coordinated, determined effort by Brazelton and other authors on the paper: research associate Fabio Rossi, PhD, and postdoctoral fellow Gilmor Keshet, PhD.
"I have tremendous admiration for their work," she said. "They worked as a team to prove these cells were in the brain."
Teamwork wasn't all that was required from Brazelton, who worked nights for more than two years to use specialized microscopes that identified bone marrow-derived cells in the brain.
"He essentially changed his circadian rhythms to complete the project," said Blau, who often met Brazelton over bagels late at night to discuss the work.
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 previous function, turned on muscle-cell-specific genes in response to appropriate stimuli. Her findings conflicted with previously established beliefs that differentiation represented a dead end for cells, and raised questions about the role of local environmental signals in determining cell fate.
Her current work 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 their ability to migrate to different organs may someday be harnessed to provide new therapies for neurodegenerative disease, stroke or other brain injury.
The results of Blau's research appear 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 different experimental techniques to track the movement of bone marrow-derived cells in mice and, like Blau, found the cells in the rodents' brains.