Like power lines in an electrical grid, long wiry projections that grow
outward from neurons — structures known as axons — form interconnected communication
networks that run from the brain to all parts of the body. But unlike an outage
in a power line, which can be fixed, a break in an axon is permanent. Each year
thousands of patients confront this reality, facing life-long losses in
sensation and motor function from spinal cord injury and related conditions in
which axons are badly damaged or severed.
New research by scientists at the Lewis Katz School of Medicine Temple
University (LKSOM) shows, however, that gains in functional recovery from these
injuries may be possible, thanks to a molecule known as Lin28, which regulates
cell growth. In a study published online in the journal Molecular
Therapy, the Temple researchers describe the ability of Lin28 —
when expressed above its usual levels — to fuel axon regrowth in mice with
spinal cord injury or optic nerve injury, enabling repair of the body’s
communication grid.
“Our findings
show that Lin28 is a major regulator of axon regeneration and a promising
therapeutic target for central nervous system injuries,” explained Shuxin Li,
MD, PhD, Professor of Anatomy and Cell Biology and in the Shriners Hospitals
Pediatric Research Center at the Lewis Katz School of Medicine at Temple
University and senior investigator on the new study. The research is the first
to demonstrate the regenerative ability of Lin28 upregulation in the injured
spinal cord of animals.
“We became
interested in Lin28 as a target for neuron regeneration because it acts as a
gatekeeper of stem cell activity,” said Dr. Li. “It controls the switch that
maintains stem cells or allows them to differentiate and potentially contribute
to activities such as axon regeneration.”
To explore the
effects of Lin28 on axon regrowth, Dr. Li and colleagues developed a mouse
model in which animals expressed extra Lin28 in some of their tissues. When
full-grown, the animals were divided into groups that sustained spinal cord
injury or injury to the optic nerve tracts that connect to the retina in the
eye.
Another set of
adult mice, with normal Lin28 expression and similar injuries, were given
injections of a viral vector (a type of carrier) for Lin28 to examine the
molecule’s direct effects on tissue repair.
Extra Lin28
stimulated long-distance axon regeneration in all instances, though the most
dramatic effects were observed following post-injury injection of Lin28. In
mice with spinal cord injury, Lin28 injection resulted in the growth of axons
to more than three millimeters beyond the area of axon damage, while in animals
with optic nerve injury, axons regrew the entire length of the optic nerve
tract. Evaluation of walking and sensory abilities after Lin28 treatment
revealed significant improvements in coordination and sensation.
“We observed a
lot of axon regrowth, which could be very significant clinically, since there
currently are no regenerative treatments for spinal cord injury or optic nerve
injury,” Dr. Li explained.
One of his goals
in the near-term is to identify a safe and effective means of getting Lin28 to
injured tissues in human patients. To do so, his team of researchers will need
to develop a vector, or carrier system for Lin28, that can be injected
systemically and then hone in on injured axons to deliver the therapy directly
to multiple populations of damaged neurons.
Dr. Li further
wants to decipher the molecular details of the Lin28 signaling pathway. “Lin28
associates closely with other growth signaling molecules, and we suspect it
uses multiple pathways to regulate cell growth,” he explained. These other
molecules could potentially be packaged along with Lin28 to aid neuron repair.
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