One of the big challenges with spinal cord injuries
is that spinal cord neurons don’t have the ability
to regrow after an injury. That’s why most spinal
paralysis in patients is permanent.
To study how peripheral neurons regrow axons — the
branches of nerve cells that transmit nerve signals
— researchers at Washington University School of
Medicine in St. Louis grow them in a dish, cut them
(as shown) and observe how they regrow. The
researchers, led by Valeria Cavalli, PhD, have
identified a master gene that enables repair of
these branches when they are cut. Cavali laboratoy.
So scientists tend to focus their research on
regrowing peripheral neurons – those that extend
from the spinal column to the tips of the hands and
feet. Peripheral neurons in the body’s extremities
have the ability to regenerate, helping people
regain some movement and sensation.
In new research, scientists at Washington University
School of Medicine in St. Louis have identified a
master gene involved in orchestrating the regrowth
of peripheral nerves. The gene works as a main
switch, making other genes “flip on” in a
domino-like fashion. Understanding how these nerves
regenerate one day may aid efforts to regrow spinal
cord neurons, the researchers said.
The findings are published online Oct. 29 in the
journal Neuron.
Surprisingly, senior author Valeria Cavalli, PhD,
associate professor of neurobiology, has shown that
injury to peripheral nerves flips on a master gene,
called hypoxia-inducible factor 1-alpha, otherwise
known as HIF-1a. This gene, in turn, activates some
200 genes involved in the regrowth of peripheral
nerves.
“What is interesting about HIF-1a is that it is
known to be sensitive to how much oxygen is in the
cell,” said Cavalli. “If the oxygen level is normal,
there isn’t much H1F-1a, but in stress conditions
such as a lack of oxygen, there is more of this gene
to protect the cell and organism from this stress.
This knowledge gave us the opportunity to use a
noninvasive tool to increase the levels of this
factor by simply decreasing the levels of oxygen.”
In the lab, Cavalli cultured neurons in a plastic
dish and used a zero oxygen environment to measure
the regrowth of nerve axons, the branches of nerve
cells that transmit nerve signals.
In other experiments, the researchers stressed out
mice, putting them in 8 percent oxygen environments
for 10 minutes, followed by normal air – about 21
percent oxygen – for 10 minutes. They repeated this
cycle six times.
What they found was that the “stressed out” neurons
responded by growing the nerve axons that connect to
the muscle (motor neurons) as well as those that
connect to the skin (sensory neurons) much better
than those that were not “stressed out” with low
oxygen.
“If you remove the oxygen for a little time, the
cell thinks ‘I’m so stressed out, I have to do
something!’ and starts activating many genes that
allow the nerves to start to regrow,” she said.
Doctors already used a similar technique in a study
of patients with chronic, incomplete spinal cord
injury — patients whose spinal cords are injured but
in such a way that some communication between the
brain and spinal cord exists, allowing limited
feeling and movement. In that study, doctors
encouraged recovery of movement by alternating
between a 9 percent oxygen environment for 90
seconds and a typical 21 percent oxygen level for 60
seconds, for 15 cycles. The idea was to “stress” the
neurons spared by injury and see if that improved
their function.
The hope for Cavalli’s team is that the low oxygen
environment also may stimulate the damaged neurons
to start regenerating and improve recovery.
Cavalli only has seen the nerve axon growth under
the microscope. She hopes to keep working to find
the right balance and answer the questions: Is less
oxygen truly beneficial? What about the time limits?
Does functional recovery occur faster and better in
mice?
“What we hope, and this is part of our future
studies, is that the hypoxia regimen also could wake
up the damaged neurons in the spinal cord to start
regrowing their axons,” she said.
For more information
Cho Y, Shin JE, Ewan EE, Oh YM, Pita-Thomas W,
Cavalli V. Activating injury-responsive genes with
hypoxia enhances axon regeneraion through neuronal
HIF-1a.
Neuron, online Oct. 29, 2015.
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Washington University School of Medicine
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