Stem-cell approach shows promise for Duchenne muscular dystrophy
 |
| L. Brian Stauffer |
Researchers have shown that transplanting stem cells derived
from normal mouse blood vessels into the hearts of mice that model the
pathology associated with Duchenne muscular dystrophy (DMD) prevents the
decrease in heart function associated with DMD. Their findings appear in the
journal Stem Cells
Translational Medicine.
Duchenne muscular dystrophy is a genetic disorder caused by a
mutation in the gene for dystrophin, a protein that anchors muscle cells in
place when they contract. Without dystrophin, muscle contractions tear cell
membranes, leading to cell death. The lost muscle cells must be regenerated,
but in time, scar tissue replaces the muscle cells, causing the muscle weakness
and heart problems typical of DMD.
The U.S. Centers for Disease Control and Prevention estimates
that DMD affects one in every 3,500 males. The disease is more prevalent in
males because the dystrophin mutation occurs on the X chromosome; males have
one X and one Y chromosome, so a male with this mutation will have DMD, while
females have two X chromosomes and must have the mutation on both of them to
have the disease. Females with the mutation in one X chromosome sometimes
develop muscle weakness and heart problems as well, and may pass the mutation
on to their children.
Although medical advances have extended the lifespans of DMD
patients from their teens or 20s into their early 30s, disease-related damage
to the heart and diaphragm still limits their lifespan.
"Almost 100 percent of patients develop dilated
cardiomyopathy," in which a weakened heart with enlarged chambers prevents
blood from being properly pumped throughout the body, said University of
Illinois comparative biosciences professor Suzanne Berry-Miller, who led the
study. "Right now, doctors are treating the symptoms of this heart problem
by giving patients drugs to try to prolong heart function, but that can't
replace the lost or damaged cells," she said.
In the new study, the researchers injected stem cells known as
aorta-derived mesoangioblasts (ADM) into the hearts of dystrophin-deficient
mice that serve as a model for human DMD. The ADM stem cells have a working
copy of the dystrophin gene.
This stem cell therapy prevented or delayed heart problems in
mice that did not already show signs of the functional or structural defects
typical of Duchenne muscular dystrophy, the researchers report.
Berry-Miller and her colleagues do not yet know why the
functional benefits occur, but proposed three potential mechanisms. They
observed that some of the injected stem cells became new heart muscle cells
that expressed the lacking dystrophin protein. The treatment also caused
existing stem cells in the heart to divide and become new heart muscle cells,
and the stem cells stimulated new blood vessel formation in the heart. It is
not yet clear which of these effects is responsible for delaying the onset of cardiomyopathy,
Berry-Miller said.
"These
vessel-derived cells might be good candidates for therapy, but the more
important thing is the results give us new potential therapeutic targets to
study, which may be activated directly without the use of cells that are
injected into the patient, such as the ADM in the current study," |
| medicalxpress.com |
Berry-Miller
said. "Activating stem cells that are already present in the body to
repair tissue would avoid the potential requirement to find a match between
donors and recipients and potential rejection of the stem cells by the
patients."
Despite the encouraging results that show that stem cells yield
a functional benefit when administered before pathology arises in DMD mouse
hearts, a decline in function was seen in mice that already showed the
characteristics of dilated cardiomyopathy. One of these characteristics is the
replacement of muscle tissue with connective tissue, known as fibrosis.
This difference may occur, Berry-Miller said, as a result of
stem cells landing in a pocket of fibrosis rather than in muscle tissue. The
stem cells may then become fibroblasts that generate more connective tissue,
increasing the amount of scarring and making heart function worse. This shows
that the timing of stem cell insertion plays a crucial role in an increase in
heart function in mice lacking the dystrophin protein.
She remains optimistic that these results provide a
stepping-stone toward new clinical targets for human DMD patients.
"This is the only study so far where a functional benefit
has been observed from stem cells in the dystrophin-deficient heart, or where
endogenous stem cells in the heart have been observed to produce new muscle
cells that replace those lost in DMD, so I think it opens up a new area to
focus on in pre-clinical studies for DMD," Berry-Miller said.
The Illinois Regenerative Medicine Institute supported this
research.
Source: University of Illinois at
Urbana-Champaign
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