Reprogramming Adult Stem Cells in the Brain

In recent years, stem cell researchers have become very adept at manipulating the fate of adult stem cells cultured in the lab. Now, researchers at the Salk Institute for Biological Studies achieved the same feat with adult neural stem cells still in place in the brain. They successfully coaxed mouse brain stem cells bound to join the neuronal network to differentiate into support cells instead.

The discovery, which is published ahead of print on Nature Neuroscience's website, not only attests to the versatility of neural stem cells but also opens up new directions for the treatment of neurological diseases, such as multiple sclerosis, stroke and epilepsy that not only affect neuronal cells but also disrupt the functioning of glial support cells.

"We have known that the birth and death of adult stem cells in the brain could be influenced be experience, but we were surprised that a single gene could change the fate of stem cells in the brain," says the study's lead author, Fred H. Gage, Ph.D., a professor in the Laboratory for Genetics and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases.

Throughout life, adult neural stem cells generate new brain cells in two small areas of mammalian brains: the olfactory bulb, which processes odors, and the dentate gyrus, the central part of the hippocampus, which is involved in the formation of memories and learning.

After these stem cells divide, their progenitors have to choose between several options – remaining a stem cell, turning into a nerve cell, also called a neuron, or becoming part of the brain's support network, which includes astrocytes and oligodendrocytes.

Astrocytes are star-shaped glia cells that hold neurons in place, nourish them, and digest parts of dead neurons. Oligodendrocytes are specialized cells that wrap tightly around axons, the long, hair-like extensions of nerve cell that carry messages from one neuron to the next. They form a fatty insulation layer, known as myelin, whose job it is to speed up electrical signals traveling along axons.

When pampered and cosseted in a petri dish, adult neural stem cells can be nudged to differentiate into any kind of brain cell but within their natural environment in the brain career options of neural stem cells are thought to be mostly limited to neurons.

"When we grow stem cells in the lab, we add lots of growth factors resulting in artificial conditions, which might not tell us a lot about the in vivo situation," explains first author Sebastian Jessberger, M.D., formerly a post-doctoral researcher in Gage's lab and now an assistant professor at the Institute of Cell Biology at the Swiss Federal Institute of Technology in Zurich. "As a result we don't know much about the actual plasticity of neural stem cells within their adult brain niche."

To test whether stem cells in their adult brain environment can still veer off the beaten path and change their fate, Jessberger used retroviruses to genetically manipulate neural stem cells and their progeny in the dentate gyrus of laboratory mice. Under normal conditions, the majority of newborn cells differentiated into neurons. When he introduced the Ascl1, which had previously been shown to be involved in the generation of oligodendrocytes and inhibitory neurons, he successfully redirected the fate of newborn cells from a neuronal to an oligodendrocytic lineage.

"It was quite surprising that stem cells in the adult brain maintain their fate plasticity and that a single gene was enough to reprogram these cells," says Jessberger. "We can now potentially tailor the fate of stem cells to treat certain conditions such as multiple sclerosis."

In patients with multiple sclerosis, the immune system attacks oligodendrocytes, which leads to the thinning of the myelin layer affecting the neurons' ability to efficiently conduct electrical signals. Being able to direct neural stem cells to differentiate into oligodendrocytes may alleviate the symptoms.

Source: Salk Institute

Related stories:

Researchers create new stem cell screening tool
Stem cell research is the next great leap in medicine. In the future, new tissue grown in a laboratory could replace a failing heart, or new cells take the place of damaged cells in the brain. Rather than using stem cells from embryonic sources, which opens difficult ethical and complicated scientific issues, scientists have been looking to adult human stem cells, culled from a person's own body. Adult stem cells are now being cultivated from various tissues in the body -- from skin, bones and even wisdom teeth.
New stem cell tools to aid drug development
SCIENTISTS have designed, developed and tested new molecular tools for stem cell research to direct the formation of certain tissue types for use in drug development programmes.
Antidepressants need new nerve cells to be effective
Researchers at UT Southwestern Medical Center have discovered in mice that the brain must create new nerve cells for either exercise or antidepressants to reduce depression-like behavior. In addition, the researchers found that antidepressants and exercise use the same biochemical pathway to exert their effects.
Alcohol consumption can cause too much cell death, fetal abnormalities
The initial signs of fetal alcohol syndrome are slight but classic: facial malformations such as a flat and high upper lip, small eye openings and a short nose.
Face transplant patient can smile, blink again
(AP) -- Transplanting faces may seem like science fiction, but doctors say the experimental surgeries could one day become routine. Two of the world's three teams that have done partial face transplants reported Friday that their techniques were surprisingly effective, though complications exist and more work is still needed.
Researcher develops novel method to grow human embryonic stem cells
(PhysOrg.com) -- The majority of researchers working with human embryonic stem cells (hESCs) – cells which produce any type of specialized adult cells in the human body – use animal-based materials for culturing the cells. But because these materials are animal-based, they could transmit viruses and other pathogens to the hESCs, making the cells unsuitable for medical use.
Largest study of its kind implicates gene abnormalities in bipolar disorder
A large genetic study of bipolar disorder has implicated machinery that balances levels of sodium and calcium in neurons. The disorder was associated with variation in two genes that make components of such ion channels. Although it's not yet known if or how the suspect genetic variation might affect the balance machinery, the results point to the possibility that bipolar disorder might stem, at least in part, from malfunction of ion channels.
Researchers Discover Tiny Cellular Antennae Trigger Neural Stem Cells
(PhysOrg.com) -- Yale University scientists today reported evidence suggesting that the tiny cilia found on brain cells of mammals, thought to be vestiges of a primeval past, actually play a critical role in relaying molecular signals that spur creation of neurons in an area of the brain involved in mood, learning and memory. The findings are published online in the journal Proceedings of the National Academy of Science.

News discussion:

Medicine & Health news