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Oxygen Key Switch in Transforming Adult Stem Cells From Fat Into Cartilage

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Duke Health News 919-660-1306

NEW ORLEANS, LA -- In their ongoing research on turning adult stem
cells isolated from fat into cartilage, Duke University Medical Center
researchers have demonstrated that the level of oxygen present during
the transformation process is a key switch in stimulating the stem
cells to change.

Their findings were presented today (Feb. 2, 2003) at the annual meeting of the Orthopedic Research Society.

Using
a biochemical cocktail of steroids and growth factors, the researchers
have "retrained" specific adult stem cells that would normally form the
structure of fat into another type of cell known as a chondrocyte, or
cartilage cell. During this process, if the cells were grown in the
presence of "room air," which is about 20 percent oxygen, the stem
cells tended to proliferate; however, if the level of oxygen was
reduced to 5 percent, the stem cells transformed into chondrocytes.

This
finding is important, the researchers say, because this low oxygen
level more closely simulates the natural conditions of cartilage, a
type of connective tissue that cushions many joints throughout the
body. However, since it is a tissue type poorly supplied by blood
vessels, nerves and the lymphatic system, cartilage has a very limited
capacity for repair when damaged. For this reason, the Duke
investigators are searching for a bioengineering approach to correct
cartilage injury.

"Our findings suggest that oxygen is a key
determinant between proliferation and differentiation, and that
hypoxia, or low oxygen levels, is an important switch that tells cells
to stop proliferating and start differentiating," said David Wang, a
fourth-year medical student at Duke, who presented the results of the
Duke research.

Farshid Guilak, Ph.D., director of orthopedic
research and senior member of the Duke team, said that the combination
of growth factors sets the adult stem cells on the right path, while
controlling oxygen levels inspires the cells to more readily transform
into chondrocytes. Without the growth factors, he said, changing oxygen
levels has no effect on the cells.

"For us, the ultimate goal is
the development of a bioreactor where we can very carefully control the
physical and chemical environment of these cells as they transform,"
Guilak said. "The results of these experiments which demonstrated the
role of oxygen levels in the process represent another important step
in achieving this goal."

Two years ago at the Orthopedic Research
Society meeting, the Duke team for the first time reported that
cartilage cells can be created from fat removed during liposuction
procedures. Not only were the researchers able to make cells change
from one type into another, they grew the new chondrocytes in a
three-dimensional matrix, a crucial advance for success in treating
humans with cartilage damage.

In their latest experiments, the
team used the materials collected from liposuction procedures performed
on multiple human donors. These materials were then treated with
enzymes and centrifuged until cells known as adipose-derived stromal
cells remained. These isolated cells were infused into
three-dimensional beads made up of a substance known as alginate, a
complex carbohydrate that is often used as the basis of bioabsorbable
dressings, and then treated with the biochemical cocktail.

Those
cells grown in hypoxic conditions saw growth inhibited by as much as 44
percent, but saw as much as an 80 percent increase in chondrocyte
differentiation.

"No one has looked at the role of hypoxia in the
creation of chondrocytes, but it made sense since cartilage normally
exists in an hypoxic environment," Wang said. "While we know oxygen
plays a role, we don't know the mechanism. The next questions to answer
are how the cells sense the level of oxygen around them and then turn
that into a metabolic change."

The researchers anticipate that
the first patients to benefit from this research would be those who
have suffered some sort of cartilage damage due to injury or trauma.
Farther down the line, they foresee a time when entire joints ravaged
by osteoarthritis can be relined with bioengineered cartilage.

"We
don't currently have a satisfactory remedy for people who suffer a
cartilage-damaging injury," Guilak said. "There is a real need for a
new approach to treating these injuries. We envision being able to
remove a little bit of fat, and then grow customized, three-dimensional
pieces of cartilage that would then be surgically implanted in the
joint. One of the beauties of this system is that since the cells are
from the same patients, there are no worries of adverse immune
responses or disease transmission."

The Duke researchers have developed several animal protocols to test how this cartilage fares in a living system.

The
research was supported by the National Institutes of Health; Artecel
Sciences, Inc., Durham, N.C.; the North Carolina Biotechnology Center,
Research Triangle Park, N.C.; and the Kenan Institute for Engineering,
Technology, and Science at North Carolina State University, Raleigh,
N.C.

Joining Wang and Guilak in the research were Beverley Fermor, Ph.D., from Duke, and Jeff Gimble, M.D., from Artecel Sciences.

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