BOB
THE PROJECT - VOL. XI - N02 - SUMMER 1998
Winning by a Nose?... Using Olfactory Ensheathing Glia in SCI
It's common knowledge, and it can be found at the start of almost any spinal
cord
regeneration article: Unlike peripheral nerves, axons (nerve fibers) in the
brain
and spinal cord do not regenerate naturally. The good news is that each of
these
articles goes on to describe some new strategy to overcome this natural
obstinance, and to report success in achieving regrowth in a laboratory test
situation. How are the scientists achieving these successes, and how will they
overcome the hurdles that remain?
As discussed at the University of Virginia workshop, there is an unprecedented
sense of optimism among scientists that restoring function by regrowing spinal
nerve fibers will be possible. Among the array of strategies being tested, the
problem of bridging a gap in the spinal cord by grafting peripheral nerve
helper
cells (Schwann cells) into the site of injury has been a major interest of
Miami
Project researcher Mary Bartlett Bunge, Ph.D.
Schwann cells are the support cells of the peripheral nerves, the nerves that
course through our arms and legs, carrying messages to muscles or sensory
information back toward the brain. They are well known to stimulate axon
regeneration by making proteins that promote nerve growth either on contact,
or
at a distance (by secreting "growth factors"). Bunge is one of the world's
foremost experts on the biology of Schwann cells.
By bringing the cells that create the growth-promoting environment in nerves
that
support regeneration into the spinal cord, which does not, Bunge and her
colleagues provide a scaffold for regrowing nerves and restoring communication
between the brain and paralyzed regions of the body. As described in the
Spring
1996 issue of "The Project", a cable of Schwann cells grafted into the spinal
cord inside a "guidance channel" stimulates thousands of nerve fibers to
regenerate across the length of the bridge.
Early tests proved that Schwann cells are much more effective in eliciting the
growth of distant nerve cells (located in the brain) if other growthpromoting
proteins are added to the bridges. Specific growth factors (scientists have
identified dozens of proteins that could be effective), used in combination
with
Schwann cell bridges or peripheral nerve grafts augment regeneration, and
attract
growth from nerve cells that modulate movements, affect autonomic functions
and
carry sensory messages. Studies from other laboratories, including a group in
Sweden led by Lars Olson, M.D., support the significance of this approach.
Ushering in a new regeneration strategy.
Despite the success of the bridging strategies, a barrier awaits the regrowing
axons at the point where the bridges end. In order to make functional
connections
with the nerve circuits beyond the bridge, the growing nerve fibers must leave
the supportive bridge and grow into the "hostile" spinal cord environment. As
Martin Schwab, Ph.D. in Zurich, and others have shown, the spinal cord
environment contains proteins that stop regenerating axons. Schwab and
colleagues
are attempting to overcome this inhibition using antibodies that prevent the
axons from seeing these stop signals.
In the May 15th issue of theJournal of Neuroscience, Bunge and her colleagues,
Almudena Ramon-Cueto, M.D., Ph.D., a visiting scientist from Spain, her
mentor,
Dr. Jesus Avila, and a postdoctoral fellow in the Bunge lab, Giles Plant,
Ph.D.,
reported results of trying a different approach. Using the basic guidance
channel
model, they transplanted a second type of helper cell just outside the
bridges.
These helper cells, called olfactory ensheathing glia (EG), are found only in
nerves that carry odor sensations to the brain. EG share some characteristics
with Schwann cells, including some of their growth-promoting properties, but
they
may also express traits that resemble astrocytes, a helper cell in the CNS
that
can inhibit axon growth. Unlike either cell type, EG also migrate extensively
within the CNS.
Throughout life, EG usher growing axons across the barrier between the
peripheral
nerve environment and the brain. Bunge's recent findings show that EG can also
usher long nerve fiber growth into surviving spinal cord regions beyond the
end
of a Schwann cell bridge. Six weeks after implantation of the guidance
channels
and injection of 400,000 EG, the investigators reported that dyes injected
into
the cervical spinal cord (in the neck, far above the transplanted bridge)
appeared in axons that had grown through, and far beyond the end of the
Schwann
cell bridges. Moreover, and quite unexpectedly, the dye was also found in
cells
on the opposite side of the bridge. This indicated that these cells had
regenerated through the bridge and over an inch farther through the spinal
cord
tissue, i.e, almost all the way to the brain.
How did the axons grow past the border and through the hostile spinal cord
environment ? The investigators showed that the EG did not stay near the ends
of
the grafts, but migrated throughout the Schwann cell cables and spinal cord,
accompanying growing axons all the way. In fact, the EG formed a second bridge
around the guidance channels, which some axons chose to cross instead of
entering
Schwann cell cables.
"Schwann cells hold great potential to enhance repair in the spinal cord,
because
we can now grow large numbers of these cells in the laboratory," said Bunge.
"Our
new results show that ensheathing glia could help overcome the barrier that
forms
between bridges of growth-promoting Schwann cells and the host spinal cord.
They
appear to escort the growing axons toward spinal cord nerve cells awaiting
signals blocked by the injury."
Gathering Other Evidence
Another study, by Geoffrey Raisman, M.D., Ph.D., also indicates that EG are an
important new strategy for improving regeneration. In a report published last
October, this British group used EG to stimulate the growth of nerve fibers
from
the brain (specifically, the cerebral cortex) past a very small area of damage
in
their spinal cord pathway. Although the exact connections made by the
regrowing
axons are not yet known, these investigators also reported that the EG
accompany
the growing fibers. Importantly, the ability of the rats to use their forepaw
in
a reaching task significantly improved, indicating that some functional
connections must have been made.
The extensive migration of the EG and accompanying axons in spinal cord tissue
is
an important finding. Ramon Cueto, who established techniques for isolating EG
cell populations, had previously shown that EG injected into spinal cord could
usher regenerating sensory axons into the cord past the normally inhibitory
peripheral nerve/spinal border. She also made advances in preparing very pure
populations of EG and expanding their numbers (hence their availability)
during
her visit to the Bunge laboratory.
The potential for promoting spinal cord regeneration using specialized cell
populations seems brighter than ever. In a related study published recently by
Bunge and her colleagues, Schwann cells genetically modified to secrete "brain
derived neurotrophic factor" (BDNF) were shown to allow nerve fibers to cross
a
completely cut spinal cord (no guidance channels were used). The BDNF promoted
the growth of some brain cells, but not others. Other laboratories have
reported
the stimulation of some spinal regeneration using other factors, and
"stimulated"
immune system cells.
The success of Bunge's EG experiment appears to lie in the combination of the
two
types of cell transplanted at the site of spinal cord injury. Researchers are
now
looking with great hope to combinations of strategies to restore significant
function in spinal cord injured animals. Such strategies, if proven to be
reliable and effective, hold great promise to ultimately be part of new
clinical
treatments.