[Note to all reporters/editors/broadcasters: The Annals of Neurology has
lifted the embargo for an article published in its online edition of June 26
by Douglas Kerr and his colleagues at Johns Hopkins University School of Medicine.
The following release is a summary of that article.]
Neurons Grown from Embryonic Stem Cells Restore Function in
For the first time, researchers have enticed transplants of embryonic stem
cell-derived motor neurons in the spinal cord to connect with muscles and partially
restore function in paralyzed animals. The study suggests that similar techniques
may be useful for treating such disorders as spinal cord injury, transverse myelitis,
amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy. The study was
funded in part by the NIH’s National Institute of Neurological Disorders and
The researchers, led by Douglas Kerr, M.D., Ph.D., of The Johns Hopkins University
School of Medicine, used a combination of transplanted motor neurons, chemicals
capable of overcoming signals that inhibit axon growth, and a nerve growth factor
to attract axons to muscles. The report is published in the July 2006 issue of Annals
"This work is a remarkable advance that can help us understand how stem cells
might be used to treat injuries and disease and begin to fulfill their great
promise. The successful demonstration of functional restoration is proof of the
principle and an important step forward. We must remember, however, that we still
have a great distance to go," says Elias A. Zerhouni, Director of the National
Institutes of Health.
“This study provides a 'recipe' for using stem cells to reconnect the nervous
system,” says Dr. Kerr. "It raises the notion that we can eventually achieve
this in humans, although we have a long way to go."
In the study, Dr. Kerr and his colleagues cultured embryonic stem cells from
mice with chemicals that caused them to differentiate into motor neurons. Just
before transplantation, they added three nerve growth factors to the culture
medium. Most of the cells were also cultured with a substance called dibutyrl
cAMP (dbcAMP) that helps to overcome axon-inhibiting signals from myelin, the
substance that insulates nerve fibers in the spinal cord.
The cells were transplanted into eight groups of paralyzed rats. Each group
received a different combination of treatments. Some groups received injections
of a drug called rolipram under the skin before and after the transplants. Rolipram,
a drug approved to treat depression, helps to counteract axon-inhibiting signals
from myelin. Some animals also received transplants of neural stem cells that
secreted the nerve growth factor GDNF into the sciatic nerve (the sciatic nerve
extends from the spine down the back of the hind leg). GDNF causes axons to grow
Three months after the transplants, the investigators examined the rats for
signs that the stem cell-derived neurons had survived and integrated with the
nervous system. The rats that had received the full cocktail of treatments — transplanted
motor neurons, rolipram, dbcAMP, and GDNF-secreting neural stem cells in the
sciatic nerve — had several hundred transplant-derived axons extending
into the peripheral nervous system, more than in any other group. The axons in
these animals reached all the way to the gastrocnemius muscle in the lower leg
and formed functional connections, called synapses, with the muscle. The rats
showed an increase in the number of functioning motor neurons and an approximately
50 percent improvement in hind limb grip strength by 4 months after transplantation.
In contrast, none of the rats given other combinations of treatments recovered
"We found that we needed a combination of all of the treatments in order to
restore function," Dr. Kerr says.
Follow-up experiments with GDNF treatment on only one side of the body showed
that, by 6 months after treatment, 75 percent of rats given the full combination
of treatments regained the ability to bear weight on the GDNF-treated limbs and
to take steps and push away with the foot on that side of the body.
"This research represents significant progress," says David Owens, Ph.D., the
NINDS program director for the grant that funded the work. "It is a convergence
of embryonic stem cell research with other areas of research that we've funded,
including work that uses combination therapies such as rolipram and dbcAMP, growth
factors, and cells to facilitate the repair of the injured spinal cord.”
Previous studies have shown that stem cells can halt spinal motor neuron degeneration
and restore function in animals with spinal cord injury or ALS. However, this
study is the first to show that transplanted neurons can form functional connections
with the adult mammalian nervous system, the researchers say. They used both
electrophysiological and behavioral studies to verify that the recovery was due
to connections between the peripheral nervous system and the transplanted neurons.
"We’ve previously shown that stem cells can protect at-risk neurons, but in
ongoing neurodegenerative diseases, there is a very small window of time to do
so. After that, there is nothing left to protect," says Dr. Kerr. "To overcome
the loss of function, we need to actually replace lost neurons."
While these results are promising, much work remains before a similar strategy
could be tried in humans, Dr. Kerr says. The therapy must first be tested in
larger animals to determine if the nerves can reconnect over longer distances
and to make sure the treatments are safe. There currently is no large-animal
model for motor neuron degeneration, so Dr. Kerr's group is working to develop
a pig model. Researchers also need to test human embryonic stem cells to learn
if they will work in the same way as the mouse cells. It has only recently become
possible to grow motor neurons from human embryonic stem cells, Dr. Kerr adds.
However, if the future studies go well, this type of therapy might eventually
be useful for spinal muscular atrophy, ALS, and other motor neuron diseases.
NINDS is a component of the National Institutes of Health (NIH) within the
Department of Health and Human Services and is the nation’s primary supporter
of biomedical research on the brain and nervous system. The NINDS mission is
to reduce the burden of neurological disease. Go to http://www.ninds.nih.gov/ for
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.