Stem Cells and Neurogenesis

by Dana Alliance for Brain Initiatives

January, 2006

Neurogenesis refers to the birth of new brain cells; not until the late 1990s did scientists prove that this process occurs in the human adult brain. Since then, and particularly in 2005, scientists have gained greater understanding of how a newborn neuron, or neural stem cell, can grow and develop into a cell that performs a specific task in the brain. Throughout the year, neurogenesis also revealed itself to be part of the healthy brain’s ongoing activities—as well as a process that can be harnessed for therapeutic purposes.

Developmental Benchmarks for Stem Cells

The adult brain contains many cells that look like young neurons maturing: they produce proteins, unique to various stages of development, that can be seen with specialized stains. But for stem cells to be useful in treating brain disorders they must function as neurons, stepping in for those that die off or are injured.

In the June 15 issue of Brain, Morten Moe and colleagues at the Karolinska Institute in Sweden show that neural stem cells go through characteristic steps as they develop into mature, functional neurons. Working with tissue from the brains of patients who had undergone surgery to correct epilepsy, the researchers cultured neural stem cells and studied them with both staining and electrophysiological techniques.

Over four weeks, the cells began to show the membrane properties and firing abilities of neurons; they developed several kinds of ion channels (through which neurons exchange electrical impulses), and, finally, synapses for two of the brain’s chief neurotransmitters. The finding is among the first to outline the changes in “behavior,” not just appearance, of adult human neural stem cells as they differentiate and mature.1

Nuclear Fallout Dates Stem Cells

Although neurogenesis has been demonstrated in several parts of the adult brain, such as the hippocampus, evidence for its occurrence in the cortex is inconclusive. The obvious solution would be to determine the age of cells—something not possible until Jonas Frisen and colleagues at the Medical Nobel Institute in Stockholm looked to the seemingly unrelated field of archaeology.

Carbon-14, or 14C, dating accurately tells the age of antiquities, but because carbon decays over thousands of years, it is less useful for dating more recent objects. However, a burst of 14C entered the Earth’s atmosphere with the testing of nuclear weapons in the 1950s, declining in measurable increments as it worked its way into the cells of plants and animals, including humans. In their study published in Cell, the researchers found that levels of 14C in cortical tissue obtained at autopsy from people born before 1950 were identical to those in the pre-nuclear-test atmosphere—meaning the cells were the same age as the individual. But in newly born blood cells, 14C concentrations matched those in the atmosphere today. The finding is credible evidence that neurogenesis does not occur in the cortex because none of the neurons in this area were younger than the individual. It also provides an elegant method for verifying the age of a cell.2

Junk DNA Distinguishes Individual Brains

When harnessing the power of stem cells, a central question is whether they truly can develop into any type of cell. In the June issue of Nature, Fred Gage and colleagues at the Salk Institute in California show that elements called retrotransposons, which make up about 15 percent of the human genome and were long thought to be genetic junk, not only change the destiny of neural stem cells but may help make each brain unique.

Elements called retrotransposons, which make up about 15 percent of the human genome and were long thought to be genetic junk, not only change the destiny of neural stem cells but may help make each brain unique.

The investigators introduced a line of human retrotransposons into cultured neural stem cells in rats. The bits of DNA embedded themselves into several genes expressed by neurons and changed the way the cells’ genes were expressed, often redirecting the cell’s path of development—turning the cell into a neuron rather than a “support” cell such as an astrocyte or oligo dendrocyte, for example. The finding suggests that retrotransposons help stem cells not only differentiate into mature cells but also bring in new traits, ensuring that no two brains—even those of identical twins—develop in exactly the same way.3

Change of fate

A cell, center, has become a neuron thanks to genetic elements called retrotransposons. These elements can change the way a stem cell develops, incorporating new traits and guaranteeing that no two brains are alike. Nuclei of other cells appear in the background. Photograph courtesy of Fred Gage, The Salk Institute

Dopamine Nixes Neurogenesis

Many studies show that antidepressants increase the rate of neurogenesis in the brain, suggesting that the absence of neurogenesis may be a factor in psychiatric disorders. Similar studies using antipsychotic drugs, however, have yielded conflicting results.

In a study in the June 15 issue of the Journal of Neuroscience, the drug haloperidol offers clues to the effects of the neurotransmitter dopamine in the normal brain and in cases of schizophrenia (the symptoms of which arise in part from the excessive actions of dopamine). Tod Kippin and colleagues at the University of Toronto showed that one role of dopamine may be to inhibit neurogenesis when necessary. The team found that haloperidol, which blocks dopamine receptors, increases the numbers of neural stem cells, and consequently new neurons, in the adult rat brain.

Turning to the culture dish, the researchers demonstrated that dopamine inhibits stem cell proliferation, that neural stem cells contain dopamine receptors, and that by binding “pre-emptively” to dopamine receptors, haloperidol can interfere with dopamine’s inhibitory effect. In the animals, the increase in neural stem cells was dramatic in the striatum, a nexus of dopamine activity. Because striatal volume is reduced in people with schizophrenia and restored with haloperidol treatment, the new study offers a novel explanation for the antipsychotic drug’s effects. It also shows that inhibition of neurogenesis, at the right time and place, may be an integral part of brain health.4 

Neurogenesis Helps Fight Brain Tumor

A provocative study in the March issue of the Journal of Neuroscience shows that the brain may employ neurogenesis to fight cancer. Using mice whose neural stem cells were “labeled” with green fluorescent protein, Helmut Kettenmann and colleagues at the Max Delbruck Center for Molecular Medicine, Berlin, infected the animals with glioblastoma cells. As the tumor developed, stem cells originating deep in the brain made their way to the site and densely clustered around the tumor. The cells also followed cancer cells that were spreading to nearby tissue.

When tested in culture, stem cells constrained the growth of the cancer cells and induced apoptosis, or programmed cell death— indicating that in the mice, the stem cells were fighting the cancer and not just replacing damaged tissue. Though older mice showed less of this spontaneous cancer-fighting ability, when injected with neural stem cells they had the same survival time as younger animals. Because glioblastoma is rare in young people and peaks in those over age 55, the findings suggest that in the young brain, neurogenesis is a powerful defense against this type of cancer—a defense that might be exploited as a treatment.5 

Gene Helps Stem Cells “Graduate”

To harness the therapeutic power of stem cells, scientists must understand how these precursors mature not only into neurons but into cells that do a particular job. In the July 27 issue of the Journal of Neuroscience, Arturo Alvarez-Buylla and colleagues identified a gene called pax6 that may play a key role in the development of dopamine-producing cells.

Working with normal, adult mice, the investigators transplanted stem cells lacking a working copy of the pax6 gene into the animals’ olfactory bulbs, an area rich in dopamine activity. The mutant stem cells colonized the olfactory bulb but failed to become either dopamine-producing cells or so-called superficial granule cells (which make an enzyme crucial to dopamine production).

The results indicate that pax6 is a gene that allows stem cells to specialize into dopamine-producing cells—important information for scientists seeking to treat diseases involving these cells, such as Parkinson’s disease.6 Another study, in the June issue of Nature Neuroscience, confirms the importance of pax6 in generating dopamine-producing cells and identifies a specific neural “niche,” called the rostral migratory stream, in which the cells originate.7 Taken together, the studies help to explain both extrinsic and intrinsic mechanisms controlling neuronal identity in adult neurogenesis. 

Embryonic Stem Cells Go Native

Stem cells derived from embryos pose an ethical dilemma, but evidence suggests that they are more versatile than those in the adult brain. Although embryonic stem cells in culture can be nudged along a particular path of development—to step in for cells that are dying, for example—the process by which transplanted cells incorporate themselves into a brain is not understood in detail.

In the May issue of Nature Biotechnology, Viviane Tabar and colleagues at Memorial Sloan-Kettering Cancer Center show that human embryonic stem cells, when grafted into the brains of young adult rats, migrated and differentiated along with the cells residing at the site of the graft—taking up positions in the same places and contributing to further neurogenesis. Because past studies hint that transplanted stem cells “fuse” with existing cells, rather than changing their own developmental destinies, the authors looked for signs of fusion—a double nucleus or extra chromosomes, for example—and found none. The authors conclude that transplanted embryonic stem cells can respond appropriately to cues from their new environment and that their offspring can replenish dying or injured neurons.8

Meanwhile, two studies offer approaches that could address the ethical concerns surrounding embryonic stem cells. In order to propagate such cells, the embryo that produces them must be destroyed. Reporting in the October 16 online issue of Nature, Robert Lanza of Advanced Cell Technology in Worcester, Massachusetts, and colleagues modified a technique already used in assisted-reproduction clinics, in which a single cell is removed from the eight-cell stage of development (before the “blastocyst” that will implant in the uterus has formed) and checked for genetic defects. Lanza’s variation, demonstrated in mice, uses this single cell to develop a line of embryonic stem cells without compromising the blastocyst’s ability to develop into an embryo.9

In the same issue of Nature, Alexander Meissner and Rudolf Jaenisch drew from previous research that showed a gene called Cdx2 to be crucial in forming the interface through which the embryo implants in the uterus. The investigators developed mouse blastocysts with altered Cdx2, which were unable to implant. The method produced an entity that could not become a viable embryo but could give rise to embryonic stem cell lines, possibly heading off concerns that a potential life is destroyed. 10 

Neurogenesis Is a Coping Technique after Stroke

Stimulating neurogenesis may be a therapeutic approach not only for neurodegenerative disease and depression but for more direct forms of brain impairment as well. Some studies show that experimentally induced stroke increases the rate of neurogenesis in young adult rats. In the August issue of the journal Stroke, researchers at University Hospital in Lund, Sweden, examined whether the same increase takes place in older brains. They found similar rates of post-stroke neurogenesis in the brains of both young and old rats, indicating that this mechanism for self-repair also operates in the aged brain.11

Five weeks after the stroke, the rats given an enriched environment showed an increase in neural stem cells and neurogenesis—a finding of great significance in understanding and treating brain damage.

A report in the June issue of the same journal shows that following a stroke, in rats at least, neurogenesis can be stimulated in a surprisingly straightforward way: by providing an enriched environment. After undergoing a procedure to mimic a stroke, adult rats were given an injection of a chemical that fastens onto dividing cells. The rats were then housed in either “enriched” environments stocked with toys, tunnels, and exercise equipment, or standard cages with food, water, and bedding only. Five weeks after the stroke, the rats given an enriched environment showed an increase in neural stem cells and neurogenesis—a finding of great significance in understanding and treating brain damage.12

New Neurons Vital to Some Kinds of Memory

Neurogenesis in the memory center called the hippocampus has been linked to learning and memory, but the details remain largely unknown. Research suggests that newly generated neurons have properties uniquely suited to the formation of new memories, and neurons “born” during a memory task are dedicated to that activity.

Martin Wojtowicz and colleagues at the University of Lethbridge, Alberta, Canada, used low-dose irradiation to stifle neurogenesis in the hippocampus of adult rats; they trained the rats in a water maze four weeks later, when no new neurons would be present. The rats returned to the maze one, two, and four weeks after training to test their memory retention. The irradiated rats learned the maze as easily as their untreated counterparts and performed as well after one week, but after two and four weeks their performance became significantly worse.

These results, published in the January issue of the journal Neuroscience, show that new neurons that are 4 to 28 days old at the time of training are required for long-term spatial memory. Treated rats easily remembered a maze test in which they could use visual cues, and irradiation either just before or just after training had no effect. The finding argues strongly that neurogenesis plays a role in the formation and consolidation of long-term, hippocampus-dependent, spatial memories.13