Salk researchers reprogram adult stem cells in their natural environment

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Salk researchers reprogram adult stem cells in their natural

environment

http://www.eurekalert.org/pub_releases/2008-06/si-srr062708.php

LA JOLLA, CA — 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 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.

Researchers who also contributed to the study include postdoctoral

researchers Nicolas Toni, Ph.D., D. Clemenson Jr, Ph.D., and

Jasodhara Ray, Ph.D., all in the Laboratory of Genetics.

The Salk Institute for Biological Studies in La Jolla, California, is

an independent nonprofit organization dedicated to fundamental

discoveries in the life sciences, the improvement of human health and

the training of future generations of researchers. Jonas Salk, M.D.,

whose polio vaccine all but eradicated the crippling disease

poliomyelitis in 1955, opened the Institute in 1965 with a gift of

land from the City of San Diego and the financial support of the

March of Dimes.