Researchers at Johns Hopkins have shown that
transplanting human stem cells into spinal cords of rats
bred to duplicate Lou Gehrig's disease delays the start of
nerve cell damage typical of the disease and slightly
prolongs life. The grafted stem cells develop into nerve
cells that make substantial connections with existing
nerves and do not themselves succumb to Lou Gehrig's, also
known as amyotrophic lateral sclerosis, or ALS. The study
is published in this week's issue of
Transplantation.
"We were extremely surprised to see that the grafted
stem cells were not negatively affected by the degenerating
cells around them, as many feared introducing healthy cells
into a diseased environment would only kill them," said
Vassilis Koliatsos, an associate professor of
pathology and
neuroscience in the School of Medicine.
Although all the rats eventually died of ALS,
Koliatsos said he believes that his experiments offer
"proof of principle" for stem cell grafts and that a more
complete transplant of cells, already being planned, along
the full length of the spine to also affect upper body
nerves and muscles might lead to longer survival in the
same rats.
"We only injected cells in the lower spine, affecting
only the nerves and muscles below the waist," he noted.
"The nerves and muscles above the waist, especially those
in the chest responsible for breathing, were not helped by
these transplanted stem cells."
The research team used so-called SOD 1 rats, animals
engineered to carry a mutated human gene for an inherited
form of ALS. As in human ALS, the rats experience slow
nerve cell death where all the muscles in the body
eventually become paralyzed. The particular SOD 1 rats in
the study developed an "especially aggressive" form of the
disease.
Adult rats not yet showing symptoms were injected in
the lower spine with human neural stem cells, which can, in
theory, become any type found in the nervous system. As a
comparison, the researchers injected rats with dead human
stem cells, which would not affect disease progression.
Both groups of rats were treated with drugs to prevent
transplant rejection.
As weight loss indicates disease onset, the rats were
weighed and tested for strength twice a week for 15 weeks.
On average, rats injected with live stem cells started
losing weight at 59 days and lived for 86 days after
injection, whereas control rats injected with dead stem
cells started losing weight at 52 days and lived for 75
days after injection.
The rats were coaxed to crawl uphill on an angled
plank, and their overall strength was calculated by
considering the highest angle to which they could cling for
five seconds without sliding backward. While all the rats
grew progressively weaker, those injected with live cells
did so much more slowly than those injected with dead
cells.
Close examination of the transplanted cells also
revealed that more than 70 percent of them developed into
nerve cells, and many of those grew new endings connecting
to other cells in the rat's spinal cord.
"These stem cells differentiate massively into
neurons, a pleasant surprise given that the spinal cord has
long been considered an environment unfavorable to this
type of transformation," Koliatsos said.
Another important feature of the transplanted cells is
their ability to make nerve cell-specific proteins and
growth factors. The researchers measured five times more of
one particular factor known as GNDF (short for glial cell
line-derived neurotrophic factor) in spinal cord fluid. The
transformation of the transplanted cells also may allow
them to deliver these growth factors to other cells in the
spinal cord through physical connections.
Cautioning that clinical applications are still far
from possible, Koliatsos said he hopes to take further
advantage of his rodents with ALS to learn as much as
possible about how human stem cells behave when
transplanted.
The researchers were funded by the National Institutes
of Health, Muscular Dystrophy Association and Robert
Packard Center for ALS Research at Johns Hopkins.
Authors on this paper are Leyan Xu, Jun Yan, David
Chen, Annie Welsh, Karl Johe, Glen Hatfield and Koliatsos,
all of Johns Hopkins; and Thomas Hazel, of Neuralstem,
Rockville, Md.
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