| After years of trial and error, scientists
have coaxed human embryonic stem cells to become spinal motor neurons,
critical nervous system pathways that relay messages from the brain to
the rest of the body. The new findings, reported online Jan. 30 in the
journal Nature
Biotechnology, are important because they provide critical
guideposts for scientists trying to repair damaged or diseased nervous
systems.
Motor neurons transmit messages from the brain and spinal cord,
dictating almost every movement in the body from the wiggling of a toe
to the rolling of an eyeball. The new development could one day help
victims of spinal-cord injuries, or pave the way for novel treatments of
degenerative diseases such as amyotrophic lateral sclerosis (ALS), also
known as Lou Gehrig's disease. With healthy cells grown in the lab,
scientists could, in theory, replace dying motor neurons to restore
function and alleviate the symptoms of disease or injury.
 Much
sooner in the future, the advance will allow researchers to create motor
neuron modeling systems to screen new drugs, says study leader
Su-Chun Zhang,
an assistant professor of anatomy and neurology in the
Stem Cell Research Program
at the Waisman Center at
UW-Madison.
Scientists have long believed in the therapeutic promise of embryonic
stem cells with their ability to replicate indefinitely and develop into
any of the 220 different types of cells and tissues in the body.
But researchers have struggled to convert blank-slate embryonic stem
cells into motor neurons, says Zhang. The goal proved elusive even in
simpler vertebrates such as mice, whose embryonic stem cells have been
available to scientists for decades.
One reason scientists have had difficulty making motor neurons, Zhang
believes, may be that they are one of the earliest neural structures to
emerge in a developing embryo. With the ticking clock of development in
mind, Zhang and his team deduced that there is only a thin sliver of
time - roughly the third and fourth week of human development - in which
stem cells could be successfully prodded to transform themselves into
spinal motor neurons.
In addition to the narrow time frame, it was also critical to expose
the growing stem cells to an array of complex chemical cocktails. The
cocktails constitute naturally secreted chemicals - a mix of growth
factors and hormones - that provide the exact growing conditions needed
to steer the cells down the correct developmental pathway. "You need to
teach the [embryonic stem cells] to change step by step, where each step
has different conditions and a strict window of time," says Zhang.
"Otherwise, it just won't work."
To differentiate into a functional spinal motor neuron, the stem
cells advanced through a series of mini-stages, each requiring a unique
growing medium and precise timing. To start, the Wisconsin team
generated neural stem cells from the embryonic stem cells. They then
transformed the neural cells into progenitor cells of motor neurons,
which in turn developed in a lab dish into spinal motor neuron cells.
The newly generated motor neurons, according to Zhang, exhibit
telltale electrical activity, a sign that the neurons, which normally
transmit electrical impulses, were functional.
The spinal motor neuron cells have survived in culture in the lab for
more than three months, says Xuejun Li, an assistant scientist in
Zhang's group, and the lead author of the study.
To determine the exact recipe for motor neuron growth, Li foraged
labs worldwide to obtain the growth factors and other natural chemicals
needed to guide cells from one stage of motor neuron development to
another. But once past a certain point, Li found that the cells kept
veering off toward different cellular destinies. After hundreds of
unsuccessful variations of growth factors and morphogens, Li was struck
by an idea: Why not apply a chemical known to be necessary for a later
stage of neuron development to a much earlier step in the process?
The hunch paid off and turned out to be the final piece of the
puzzle.
The discovery, says Zhang, demonstrates that human stem cells do not
necessarily differentiate in linear fashion, as scientists always
believed. Rather, a series of complex overlapping changes may well be
the developmental norm in higher vertebrates such as humans.
"We cannot simply translate studies from animal to humans," says
Zhang.
The next step, Li says, will be to test if the newly generated
neurons can communicate with other cells when transplanted into a living
animal. The team will first test the neurons in chicken embryos.
While the new results are promising and provide access to critical
cells that may one day be used in therapy, it will likely be many years
before they can be tested in humans, Zhang says.
The work was supported by the
Amyotrophic Lateral Sclerosis Association, the nonprofit
organization Hope for ALS, and
the Neuro-Immune Dysfunction Syndrome
Research Institute of the National
Institutes of Health.
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