UC study explores obscure stem cells / Scientists hope they'll serve as brain repair kit
Published 4:00 am, Thursday, February 19, 2004
A mysterious type of stem cell found in the brain appears to be a possible wellspring of fresh nerve cells and, when something goes haywire, the starting point of a common form of tumor, scientists are reporting.
The finding lays new ground for understanding the fundamental biology of stem cells in the adult brain. Scientists hope these cells and the signaling molecules that govern their fate might someday serve as a repair kit for treating brain injury, strokes or neurodegenerative diseases such as Parkinson's.
The study resulted from a collaboration of neuroscientists and brain surgeons at UCSF Medical Center, led by Dr. Nader Sanai, a 26-year-old neurosurgery resident. Dr. Mitchel Berger, chair of neurosurgery, and stem- cell expert Arturo Alvarez-Buylla were senior authors.
The study appears in today's issue of the journal Nature.
Earlier work by Alvarez-Buylla and colleagues showed that the same type of brain cell, known as astrocytes, can generate new nerve cells in the brains of adult mice. The new study is the first to describe the function of these astrocyte stem cells in human brains.
Stem cells are primitive building blocks that can be shaped into the myriad kinds of mature cells that make up the body. All-purpose embryonic stem cells are the best known, and most controversial, but adult stem cells also have been found in virtually all organs.
In rodents and other animals, astrocytes migrate by the thousands every day in long chains from a region known as the subventricular zone to the olfactory bulb, the part of the brain involved in the sense of smell. But there is no such migration in people, and the human cells have no apparent role in the capacity for smell.
Their function in healthy people, in fact, is unknown, despite the flood of attention in recent years to stem cell biology. Experts speculate that the human brain simply lost its self-renewing stem cell function. Just how this happened -- and whether the regenerative power of the stem cells can be regained for therapy -- is an open question.
"Even though a lot is known about stem cells in other animals, relatively little is know about them in the human brain," Sanai said during an interview. Although the cells do not replenish the olfactory region in people, "they could be generating neurons serving another target which we have yet to identify," he added.
For the new study, the researchers examined tissues from 45 autopsied brains and from 65 patients who had undergone surgery. The work was inspired partly by many years of clinical observations suggesting that gliomas, a common form of brain tumor, nearly always involve the subventricular zone, areas of the brain adjacent to the fluid-filled cavities.
Besides their versatility, stem cells also are known for their power to make copies of themselves. The speculation now is that cancer arises when the factors that ordinarily hold the stem cells in check become disabled, or when cancer-promoting signals overwhelm the cells.
"That is the hidden message in this manuscript," Berger said, calling the discovery of a candidate source of malignant cells deep in the brain a "Holy Grail of neurobiology."
The critical next steps, he said, will be to prove the cancer link in the laboratory and identify what can drive a pool of stem cells to transform into cancer. If the signals can be identified, it might be possible to fashion new cancer-blocking drugs from them.
Yale University neurobiologist Pasko Rakic, author of a commentary on the research in the same issue of Nature, said scientists were still a long way from unraveling the circuitry that shapes the fate of the brain's stem cells. Unlike salamanders, he noted, which readily can regenerate large chunks of their brain, humans have all but lost that native capability. "The important question is why," he said.