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Chronic wounds, which include bedsores, are a common and
potentially life-threatening problem.
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A study conducted by NYU School of Medicine researchers,
in collaboration with the Wound Healing Program at Columbia
University, sheds new light on the molecular mechanisms
underlying the development of chronic wounds. The findings
may help clinicians predict which wounds are likely to
become chronic -- a key bit of information, since the sooner
treatment is started, the better the outcome. The research
also raises the hope for new treatments for chronic wounds
by identifying possible targets for intervention.
Chronic wounds, which include bedsores, are a common and
potentially life-threatening problem, typically occurring in people
with diabetes or poor circulation, the elderly, and anyone who is
bedridden or wheelchair-bound. Bedsores -- also known as pressure
sores or pressure ulcers -- have been estimated to affect about five
to ten percent of hospital patients, 13 percent of nursing home
residents, and up to 39 percent of spinal cord injury patients in
the United States. Chronic wounds can lead to widespread infections
and limb amputations, says Marjana Tomic-Canic, Ph.D., Associate
Professor of Dermatology and Microbiology at NYU School of Medicine,
the study's lead author.
Studying tissue taken from chronic wounds in humans, the
researchers discovered that skin cells get stuck in the middle of
the normal healing process and cannot migrate to the wound site. The
stalling of the healing process, the researchers discovered, is
caused by overabundance of a molecule called c-myc (a product of the
ubiquitous myc gene, which has been implicated in many human
cancers). This molecule is known to suppress cell migration and to
cause the skin to thicken, obstructing reparative cells from
reaching the edge of the wound.
The cause of c-myc overproduction was then traced one step up the
molecular pathway to beta-catenin, a critical regulator of cell
behavior. According to the researchers, beta-catenin activates the
production of c-myc as well as other pathways that affect the
migration, growth, and regulation of skin cells.
This is the first study to investigate the roles of c-myc and
beta-catenin in impairment of wound healing in humans. It is
published in the July 1 issue of the American Journal of Pathology.
In normal skin, cells are tightly stuck together in order to
create a barrier between the body and the outside world, keeping
water in and infections out. But when a wound occurs, skin cells
from lower layers loosen from their neighbors and start migrating to
the wound site and dividing rapidly. Dr. Tomic-Canic and her
colleagues found that in skin with chronic wounds, the cells
multiply at a higher rate than usual, yet they are unable to migrate
into the wound to close it. Instead, they form thickened layers
around the edge, much like a callus or a corn.
Something else also goes awry in chronic wounds, according to the
study. As skin cells move upwards, they normally lose their nuclei
and form sturdy layers of cross-linked proteins, creating a
protective layer over the wound. But in chronic wounds, the
researchers found, skin cells are unable to progress to this stage
of differentiation, and their nuclei remain present.
"The biology seems to be stuck in the middle of these two
processes, and can't seem to complete either of them," says Dr.
Tomic-Canic.
In the next step of their research, team will try to figure out
what causes beta-catenin to accumulate in chronic wounds. In the
meantime, they say, the molecules they have identified may make the
treatment of chronic wounds more effective.
Doctors have few effective therapies for treating chronic wounds.
Usually, the non-healing edge of the wound is surgically removed in
order to get rid of the bad tissue. However, it can be difficult to
determine how much tissue should be removed. Then, dressings, which
may contain growth factors or living cells that skin cells require
for healing, are placed over the wound.
If skins cells could be tested for high levels of molecules such
as c-myc, says Dr. Tomic-Canic, physicians would be able to tell
which cells were already stuck in the non-healing state. Surgeons
could then remove this unresponsive tissue and know exactly where
the healthy tissue starts. "The skin cells within the edge of the
wound that do not have these pathogenic markers or have very little
are the million-dollar cells, which you really want to target in
therapy," says Dr. Tomic-Canic.
The findings may also be useful in clinical trials of new
therapies for chronic wounds, to make sure that the treatments are
targeting the right types of cells. In the future, molecules such as
c-myc and beta-catenin could be the focus of medications, cutting
the chain of wound development before it advances.
The other authors of the new study are Olivera Stojadinovic,
Constantinos Vouthounis, Brian Lee, Ankit Merchant, and Robert
D.Galliano from NYU; Harold Brem from Columbia University; John
Fallon from Mount Sinai School of Medicine; and Michael Stallcup
from the University of Southern California.
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