The study, conducted by investigators in the UCSF Department of Neurological Surgery, is the cover story in the Feb. 19 issue of Nature.
The researchers conducted their study on brain specimens (from neurological resections and autopsies) containing the lining of the brain's fluid-filled cavity, a region known as the subventricular zone. There, they discovered a sheet of the brain's most ubiquitous cell, the astrocyte - traditionally thought of as a supportive cell for neurons in the adult brain – and determined in cell culture studies that the cell has the capacity to function as a neural stem cell. They also detected fresh, young neurons within the astrocytic region that likely are the progeny of these stem cells, the researchers say.
Scientists have long viewed astrocytes as foot soldiers to the brain's far more glamorous neurons, which orchestrate thought, feeling, and movement. But the researchers determined in their cell culture studies that the star-shaped astrocytes of the region have the ability to perpetually self-renew and produce the three types of cells in the brain - neurons, oligodendrocytes (which insulate nerve cell extensions, or axons) and astrocytes.
Just what function these adult stem cells perform in the subventricular zone is unclear. It's possible, the scientists say, that the cells remain in the region for some unknown purpose. It's also possible they produce fresh neurons that migrate to other parts of the brain, replenishing neurons there throughout adult life.
In either case, the scientists want to determine if certain molecular signals or growth factors could be used to coax the cells to generate neurons in a culture dish, with the goal of transplanting them into patients to regenerate tissue damaged by conditions such as Parkinson's disease, Alzheimer's disease and stroke. Likewise, they want to ascertain whether regular astrocytes in other brain regions could be induced through molecular signaling to differentiate into fresh neurons, as well.
"Neurosurgery has traditionally been a field of ablation, one of excising or eliminating a lesion, albeit very precisely, delicately, and elegantly. Here we have a new reason to hope that, one day, there could be neuroregeneration - a new mode of therapy where we could replenish brain function that has been lost through either neurologic disease or its subsequent surgical treatment," says the lead author of the study, Nader Sanai, MD, a UCSF resident neurosurgeon and neuroscientist in the laboratory of senior author Arturo Alvarez-Buylla, PhD, UCSF professor of neurological surgery.
"We want to figure out what makes the astrocytes in the subventricular zone special," says Sanai. "Are there other astrocytes in the human brain with the potential to function as stem cells? If we identify the necessary molecular signals, can we unlock this potential in normal astrocytes and make them function as stem cells? The clinical implications of these concepts are at once fascinating and potentially powerful."
Exploring the origin of glial brain tumors
On another clinical front, the team is investigating whether disregulated astrocytic stem cells could be the cause of the most common type of human brain tumor, the glioma, which is thought to be derived from astrocytes. Because these cancers generally are not detected until they are advanced, when symptoms have begun to develop, scientists do not know where - or what - initiates the process of uncontrolled cell replication that leads to the formation of these brain tumors. Some evidence suggests, say the UCSF researchers, that the tumors may originate around the lining of the ventricles.
"On occasion, we do have the opportunity to see brain images of patients with tumors at an early stage of development, and in these cases I have noticed that the tumors are often associated with the ventricular system, particularly in the subventricular zone," says co-senior author Mitchel S. Berger, MD, professor and chairman of the Department of Neurological Surgery, who treats patients at UCSF Medical Center and is director of the UCSF Brain Tumor Research Center. The UCSF Department of Neurological Surgery is one of the world's largest neurosurgical programs and leads the nation in research funding from the National Institutes of Health.
"The results presented in this study suggest that astyrocytic stem cells in the subventricular zone could be the source of gliomas," says Berger. To investigate this possibility, he says, the UCSF team is going to introduce the genetic defects known to promote brain tumor progression into astrocytic stem cells in cell culture and, ultimately, in animal model systems, to see if they develop the equivalent of human tumors. If they do form tumors, he says, the next goal would be to develop therapeutic strategies aimed at blocking astroyctic stem cell proliferation, or division, at an early stage of tumor development.
It would not be surprising if human astrocytic stem cells were predisposed to malignant transformation, says Sanai. The cells are constantly dividing, and thus going through the cell-cycle repeatedly, each cycle increasing the odds of a cell developing genetic errors. The accumulation of errors would make a cell more likely to slip into disregulated replication overdrive, the hallmark of cancer.
"If this theory proves true," says Sanai, "it would open up a whole new avenue in brain tumor research."
Building on previous research
The study builds upon previous research by Alvarez-Buylla, who reported in 1999 that astrocytes function as adult stem cells in the subventricular zone of mice, churning out fresh, young neurons that then migrate to the olfactory bulb in a unique pattern of movement he called chain migration. The constant replenishment of young neurons, scientists suspect, maintains the animals' keen sense of smell. The finding was one of the first reports identifying adult stem cells in the brain of any mammal as astrocytic (Cell, June 11, 1999). Other scientists have subsequently determined that neural stem cells in the subventricular regions of rats, dogs, sheep, and monkeys also generate neurons that migrate in a chain-like fashion to the olfactory bulb.
Since then, scientists have demonstrated that adult stem cells exist in the subventricular zone of the human brain, but they have never detected the identity, organization or function of these cells. The current study is the first to not only discover these characteristics, but also to isolate human astrocytes that could function as neural stem cells.
At the outset of the study, the researchers discovered that the outer walls of the brain's central cavities, or ventricles, were lined by a ribbon of constantly dividing astrocytes. They also detected fresh, new neurons in the region. Much to their surprise, however, the researchers determined that these young neurons did not form migratory chains to the olfactory bulb. Exactly where the progeny of this ribbon of neural stem cells might go, if anywhere, is still unknown.
The fact that the human brain does not maintain the pattern of chain migration seen in so many other animals, including primates, is surprising, says Sanai, given the evolutionary propensity of animals to conserve anatomical structures. At the same time, he says, it makes sense, given humans' relatively weak sense of smell.
"The fact that we're not seeing a mass exodus of newly-formed neurons to the human olfactory bulb suggests either that these neurons aren't doing anything when they are born, which is a possibility, or they are doing something entirely novel in the human brain," says Sanai.
In their study of the subventricular zone, the researchers worked with healthy brain tissue from 65 tissue samples from neurosurgical resections (the margins always taken to safeguard a patient) and 45 samples from autopsies. After discovering the ribbon of astrocytes along the lining of the ventricles, they succeeded in isolating the astrocytes from the tissue's dense network of mixed brain cells. Then, they conducted a series of experiments in the culture dish that revealed these cells have the properties of adult neural stem cells (i.e., the ability to produce the various cells of a given organ, in this case the brain).
First, they showed that when the cells were exposed to growth factors they could create structures called neurospheres, raspberry-like globules that can self-perpetuate and give rise to all three brain cell types - neurons, oligodendrocytes and astrocytes. Then, they demonstrated that individual subventricular zone astrocytes, grown upon a feeding layer of normal astrocytes from the human brain cortex, could produce new neurons without requiring added growth factors.
The relative ease with which the astrocytes were driven to function as adult stem cells in the second experiment was notable, says Sanai. It suggests, he says, that some factor is being secreted by the normal cortical astrocytes that induce these adult neural stem cells to produce new neurons.
The answers await. "From the laboratory to the operating room, from mice to humans." he reflects. "Many investigators and clinicians gravitate towards stem cells because they are scientifically unique and potentially powerful. They inspire in us new hope. The first step, however, will always be to simply understand their biological nature."
Other co-authors of the study are Anthony D. Tramontin, PhD, of the UCSF Developmental and Stem Cell Biology Program; Alfredo Quinones-Hinojosa, MD, Nicholas. M. Barbaro, MD, Nalin Gupta, MD, PhD, Sandeep Kunwar, MD, Michael T. Lawton, MD, Michael W. McDermott, MD, and Andrew T. Parsa, MD, PhD, all of the UCSF Department of Neurological Surgery and Brain Tumor Research Center; and Jose Manuel-Garcia Verdugo, PhD, of the Instituto Cavanilles, University of Valencia, Spain.
The study was funded by the William Siebrandt glioblastoma fund and grants from the National Institutes of Health, the Howard Hughes Medical Institute and the American Brain Tumor Association.
The adult stem cell research under way in the Alvarez-Buylla lab is strongly supported by funds from Frances and John Bowes. More broadly, the UCSF Developmental and Stem Cell Biology Program was launched in August 2002 with a matching grant from Andy Grove, the chairman of Intel Corp.
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