Our
Stem Cell Studies Show
How the Center Works
Packard Center scientists have been quick to investigate the potential
of stem cells, both adult and embryonic, as a repair technique.
As important, they’re showing that, as nothing else, stem
cells can clarify how nervous system cells develop and how they
might go awry in ALS. Stem cell science and techniques are complex,
though: questions of which type are most useful, what delivery system
to use, how best to monitor behavior and safety loom large. The
work takes many minds, many hands—just what the Center does
best.
| 1 |
As the Center opened, a core team of Jeffrey Rothstein, Douglas
Kerr and Nicholas Maragakis began to chart long term plans for
stem cells in ALS. Early studies with embryonic stem (ES) cells
on a virus-based rat model of neurodegeneration that Kerr used
showed a remarkable lessening of paralysis—an eye-widening
result, but only a first step on the road to ALS repair. |
| 2 |
Kerr proved that stem cells sparked the rats’ improvement.
But for stem cell therapy, a more controlled, consistent approach
is in order. He needed to find the most effective stem cell
types, to see if they morph into true motor neurons and if they
could form right relationships with muscle. Meanwhile, Packard
colleagues had made key discoveries about cells surrounding
motor neurons—glial cells—and their role in promoting
death of ALS motor neurons. What would be the good of growing
new motor neurons in a “bad” environment? The problems
were considerable. |
| 3 |
Using model rats, Kerr seeded their spinal cords with more
advanced, neuron-leaning ES cells. The cells soon formed healthy
motor neurons, but in that foreign environment, wouldn’t
travel beyond the spinal cord until the team—with Marie
Filbin’s insights (below)—tried a block-reversing
drug. |
| 4 |
Now motor neurons pushed outside the spinal cord, but they
still didn’t reach out to muscle. After parallel research
by Rothstein, Maragakis and Höke discovered that some stem
cells release proteins that both encourage neuron growth and
help resist damage, Kerr and colleagues placed that second type
of stem cell in strategic places near rat muscle. Then... success!
The motor neuron-muscle hookup not only looked normal, it also
worked! Paralyzed rats improved. |
 |
Doug Kerr mapped out a five-year project to turn stem cells
into fully functioning motor neurons in an ALS model.* |
 |
John Gearhart contributed embryonic stem (ES) cells and invaluable
expertise in their use. |
 |
Elegant work by Don Cleveland, Larry Goldstein and Jean-Pierre
Julien showed that, in ALS, the cells surrounding motor neurons—glia—promote
motor neuron death. Fortunately, an abundance of healthy glia
can protect motor neurons, suggesting normal glial stem cells
may play a part in therapy. |
 |
Center advisor Tom Jessell offered know-how in pushing stem
cells into becoming motor neurons. |
 |
New neurons are repelled by the myelin that insulates the
adult nervous system. But Marie Filbin’s research produced
an agent to overcome that, so they can grow outward. |
 |
Jeff Rothstein’s research showed neural stem cells secrete
growth factors that nurture injured motor neurons. |
 |
Ahmet Höke’s work found which growth factors encourage
injured peripheral neurons to regrow and in what time frame. |
 |
Mahendra Rao and Nick Maragakis have clarified the nature
of glial stem cells and how they protect motor neurons, readying
them as a possible stem cell therapy. |
*The MDA, ALSA and Project ALS provided
additional funding for Kerr’s work. |
