Purified stem cells restore muscle in mice with muscular dystrophy
By injecting purified stem cells isolated from adult skeletal muscle,
researchers have shown they can restore healthy muscle and improve
muscle function in mice with a form of muscular dystrophy. Those
muscle-building stem cells were derived from a larger pool of so-
called satellite cells that normally associate with mature muscle
fibers and play a role in muscle growth and repair.
In addition to their contributions to mature muscle, the injected
cells also replenished the pool of regenerative cells normally found
in muscle. Those stem cells allowed the treated muscle to undergo
subsequent rounds of injury repair, they found.
"Our work shows proof-of-concept that purified muscle stem cells can
be used in therapy," said Amy Wagers of Harvard University, noting
that in some cases the stem cells replaced more than 90 percent of
the muscle fibers. Such an advance would require isolation of stem
cells equivalent to those in the mouse from human muscle, something
Wagers said her team is now working on.
Satellite cells were first described decades ago and have since
generally been considered as a homogeneous group, Wagers said. While
anatomically they look similar under a microscope, they nonetheless
show considerable variation in their physiology and function. In a
previous study, Wagers' identified a set of five markers that
characterize the only subset of satellite cells responsible for
forming muscle, which they also refer to as skeletal muscle
precursors or SMPs.
In the new study, the researchers analyzed the stem cell and
regenerative properties of those SMPs. When engrafted into muscle of
mice lacking dystrophin, purified SMPs contributed to up to 94
percent of muscle fibers, restoring dystrophin expression and
significantly improving muscle structure and contractile function,
they report. (The dystrophin gene encodes a protein important for
muscle integrity. Mice lacking dystrophin, also known as mdx mice,
are a model for Duchenne Muscular Dystrophy, the most prevalent form
of muscular dystrophy.)
" Importantly, high-level engraftment of transplanted SMPs in mdx
animals shows therapeutic value—restoring defective dystrophin gene
expression, improving muscle histology, and rescuing physiological
muscle function," the researchers said. "Moreover, in addition to
generating mature muscle fibers, transplanted SMPs also re-seed the
satellite cell niche and are maintained there such that they can be
recruited to participate in future rounds of muscle regeneration.
"Taken together, these data indicate that SMPs act as renewable,
transplantable stem cells for adult skeletal muscle. The level of
myofiber reconstitution achieved by these myogenic stem cells exceeds
that reported for most other myogenic cell populations and leads to a
striking improvement of muscle contraction function in SMP-treated
muscles. These data thus provide direct evidence that prospectively
isolatable, lineage-specific skeletal muscle stem cells provide a
robust source of muscle replacement cells and a viable therapeutic
option for the treatment of muscle degenerative disorders."
Wagers noted however that there may be complications in the delivery
of cell therapy in humans, particularly for those with conditions
influencing skeletal muscle throughout the body. Even so, the new
findings present an "opportunity to understand what happens [to these
regenerative cells] in disease and identify factors and pathways that
may boost their activity," she said. "We may get a handle on drugs
that could target muscle impairment" not only in those with muscular
dystrophies, but also in elderly people suffering from the muscle
wasting that comes with age.
###
The researchers include Massimiliano Cerletti, Joslin Diabetes
Center, Boston, MA, Harvard University, and Harvard Stem Cell
Institute, Cambridge, MA; Sara Jurga, Joslin Diabetes Center, Boston,
MA, Harvard University, and Harvard Stem Cell Institute, Cambridge,
MA; Carol A. Witczak, Joslin Diabetes Center, Boston, MA; Michael F.
Hirshman, Joslin Diabetes Center, Boston, MA; Jennifer L. Shadrach,
Joslin Diabetes Center, Boston, MA, Harvard University, and Harvard
Stem Cell Institute, Cambridge, MA; Laurie J. Goodyear, Joslin
Diabetes Center, Boston, MA; and Amy J. Wagers, Joslin Diabetes
Center, Boston, MA, Harvard University, and Harvard Stem Cell
Institute, Cambridge, MA.
Public release date: 10-Jul-2008
Contact: Cathleen Genova
cgenova@cell.
617-397-2802
Cell Press
http://www.eurekale
More:
Muscle stem cell transplant boosts diseased muscle function and
replenishes stem cell pool
BOSTON – July 10, 2008 – Researchers at the Joslin Diabetes Center
have demonstrated for the first time that transplanted muscle stem
cells can both improve muscle function in animals with a form of
muscular dystrophy and replenish the stem cell population for use in
the repair of future muscle injuries.
"I'm very excited about this," said lead author Amy J. Wagers, Ph.D.,
Principal Investigator in the Joslin Section on Developmental and
Stem Cell Biology, principal faculty member at the Harvard Stem Cell
Institute and Assistant Professor of Stem Cell and Regenerative
Biology at Harvard University. "This study indicates the presence of
renewing muscle stem cells in adult skeletal muscle and demonstrates
the potential benefit of stem cell therapy for the treatment of
muscle degenerative diseases such as muscular dystrophy."
The study was designed to test the concept that skeletal muscle
precursor cells could function as adult stem cells and that
transplantation of these cells could both repair muscle tissue and
regenerate the stem cell pool in a model of Duchenne muscular
dystrophy, she said. The research is published in the July 11 issue
of Cell.
Duchenne muscular dystrophy is the most common form of the disease
and is characterized by rapidly progressing muscle degeneration. The
disease is caused by a genetic mutation and there is currently no
cure.
The data from this new study demonstrate that regenerative muscle
stem cells can be distinguished from other cells in the muscle by
unique protein markers present on their surfaces. The authors used
these markers to select stem cells from normal adult muscle and
transferred the cells to diseased muscle of mice carrying a mutation
in the same gene affected in human Duchenne muscular dystrophy.
"Once the healthy stem cells were transplanted into the muscles of
the mice with muscular dystrophy, they generated cells that
incorporated into the diseased muscle and substantially improved the
ability of the treated muscles to contract," said Wagers. "At the
same time, the transplantation of the healthy stem cells replenished
the formerly diseased stem cell pool, providing a reservoir of
healthy stem cells that could be re-activated to repair the muscle
again during a second injury."
According to the paper, these cells provide an effective source of
immediately available muscle regenerative cells as well as a reserve
pool that can maintain muscle regenerative activity in response to
future challenges.
"This work demonstrates, in concept, that stem cell therapy could be
beneficial for degenerative muscle diseases," Wagers said.
Wagers also said the study will lead to other studies in the near-
term that will identify pathways that regulate these muscle stem
cells in order to figure out ways to boost the normal regenerative
potential of these cells. These could include drug therapies or
genomic approaches, she said. In the long-term, the idea will be to
replicate these findings in humans.
"This is still very basic science, but I think we're going to be able
to move forward in a lot of directions. It opens up many exciting
avenues," she said.
The Wagers Lab at Joslin studies both hematopoietic stem cells, which
constantly maintain and can fully regenerate the entire blood system,
as well as skeletal muscle stem cells, involved in skeletal muscle
growth and repair. The work is aimed particularly at defining novel
mechanisms that regulate the migration, expansion, and regenerative
potential of these two distinct adult stem cells.
Public release date: 10-Jul-2008
Contact: Kira Jastive
kira.jastive@
617-732-2418
Joslin Diabetes Center
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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