By David N. Leff
Inside your skull, your 3-pound brain floats on a sea of cerebrospinal fluid.
Besides buoying up that convoluted cluster of gray and white matter, the clear, colorless lubricant acts as a shock absorber for blows to the head. An average skull contains 100 to 150 milliliters of the liquid, which renews itself three to four times a day.
The labyrinthine network of cisterns that holds this dollop of cerebrospinal fluid consists of ventricles. A seamless membrane, the ependymal layer, lines their walls and continues south into the center of the spinal cord.
A stem cell just discovered in that inner-surface layer might be driving one last nail into the coffin of the long-standing dogma that adult brain neurons can't regenerate. (See BioWorld Today, Nov. 18, 1998, p. 1.)
An article in the current issue of the twice-monthly journal Cell, dated Jan. 8, 1999, reports: "Identification of a neural stem cell in the adult mammalian central nervous system." Its senior author is neuroscientist Jonas Frisin of the Karolinska Institute in Stockholm.
"This study shows us," Frisin told BioWorld Today, "that for the first time in the scientific literature, we have identified which cells are the neural stem cells. It has been difficult, however," he added, "to identify and locate them, as stem cells are typically dormant. So their identity in the adult nervous system, as in many other tissues, has been unknown."
His Karolinska colleague, neuroscientist Ann Marie Janson, picked up that thread: "The dogma that the brain does not regenerate its neurons," she told BioWorld Today, "has already started to be attacked by several other researchers. The Cell paper is another piece in that puzzle. You can even call this perhaps the last battle with that dogma."
She continued: "Because everyone was asking before, if the brain can make new neurons, where is the stem cell from which they come? If ours is at least one neural stem cell, we can't exclude that there are other ones, too. We have information that we haven't published," Janson went on, "to say that the stem cells that we know of can probably give rise to neurons in the adult brain."
Frisin serves as co-founder and research director of a Stockholm-based start-up company, NeuroNova AB, which he and Janson launched last June. She is the new firm's CEO.
The two are principal inventors of several patents now pending internationally and in the U.S., Janson said. Their claims, she added, "deal with the basic identification and localization of these stem cells, methods of how to study them, assays in vitro and in vivo, and aspects all the way up to the clinic."
Although Janson and Frisin both continue in their academic posts at the Karolinska NeuroNova holds title to their intellectual property.
Olfaction: More Than Smell Alone
"In this [Cell] study," the paper noted, "we demonstrate that ependymal cells are neural stem cells, and provide novel insights into how stem cells participate in the response to CNS injury."
One salient brain region to which Frisin and his co-authors tracked their migrating ventricular stem cells was the olfactory bulb.
Besides communicating the sense of smell, Janson pointed out, "the special thing is that the olfactory bulb has been widely accepted in the scientific community as a site of new neurons appearing. But the source where these new neurons came from was not known.
"It was also acknowledged," she went on, "that these new neurons end up in that bulb, after following a stream of cells migrating in the brain." Frisin and his co-authors identified them as the very neurons being renewed in the olfactory bulb.
One key finding in their Cell paper is that when activated by an injury to the central nervous system (CNS), these ependymal stem cells begin to divide. Following an experimental injury (under anesthetic) to the spinal cords of rats, their rate of cell division increased 50-fold in a single day. (See BioWorld Today, Dec. 18, 1997, p. 1.)
"Probably there are molecular signals in the environment that tell the neural stem cells whether they should turn into a neuron or into a glia," Janson observed. "What Frisin has shown here is that when they label these stem cells and see them go to some areas of the brain, they become neurons. And when they go into some other areas, this time in the spinal cord after an injury, then they all become glial cells.
"Of course, this is just the first clue. Before, it was not known exactly where the glia came from, before the glial scar in the spinal cord.
"And secondly," she went on, "there may be possibilities to intervene therapeutically with these stem cells, so they could go into particular neuronal phenotypes. But this is for the future."
Implications For Patients
"I think it's a little bit early to talk about humans," Janson said, "until we really have done some clinical studies. Already today," she pointed out, "there is transplantation of progenitor or embryonal stem cells into human brains. Of course, the ethical problems of such fetal tissue transplants would not be present if instead you used adult neural stem cells.
"And there are a lot of other advantages," she added, "perhaps because the immunological system would not be reacting if you took out stem cells from an individual, for example, and grew them ex vivo, similar to growing a victim's own skin cells after burn injury."
Janson considers that the neurodegenerative diseases, notably Alzheimer's and Parkinson's, "are probably the most important ones, not only because [of the expense to] society and the suffering of individual patients, but also because there are no cures.
"So those diseases are of course the top priority for NeuroNova now," she went on. "We're working with various species of animal models besides rats, to research them. And we are looking at other strategies as well, including different assays to help discover small-molecule therapeutic drugs, for example, that can affect the stem cells in the brain." n