Duke Scientists Discover Key to Growing New Stem Cells
DURHAM, N.C. -- Scientists at Duke University Medical Center
have demonstrated they can grow human stem cells in the
laboratory by blocking an enzyme that naturally triggers stem
cells to mature and differentiate into specialized cells.
The discovery may enable scientists to rapidly grow stem
cells and transplant them into patients with blood disorders,
immune defects and select genetic diseases, said the Duke
Stem cells are the most flexible cells in the body,
continually dividing into new stem cells or into specialized
cells that carry out specific roles in the body. But little is
known about how stem cells choose their fate. The Duke team
focused on "hematopoietic" or blood stem cells.
In their study, the investigators discovered that an enzyme,
aldehyde dehydrogenase (ALDH), stimulates hematopoietic stem
cells to mature and transform into blood or immune cells, a
process called differentiation. They inhibited this enzyme in
stem cell cultures and successfully increased the number of
stem cells by 3.4 fold. Moreover, they demonstrated the new
stem cells were capable of fully rebuilding the blood-forming
and immune systems of immune-deficient mice.
Results of the study are published on line and will be
published in the August 1, 2006, issue of the Proceedings of
the National Academy of Sciences.
"Our ability to treat human diseases is limited by our
knowledge of how human stem cells determine their fate -- that
is, whether they maintain their ability to self-renew or
whether they go on to become specialized cells," said John
Chute, M.D., associate professor of medicine in the Duke Adult
Bone Marrow and Stem Cell Transplant Program. "Unraveling the
pathways that regulate self-renewal or differentiation in human
stem cells can facilitate our ability to expand the growth of
human stem cells for therapeutic uses."
Currently, patients who require stem cell transplants are
given either bone marrow from adult donors, umbilical cord
blood derived from newborn babies, or stem cells from blood.
But stem cells are scarce, representing less than 0.01 percent
of the bone marrow cell population. Likewise, cord blood units
frequently lack sufficient numbers of stem cells to rebuild a
patient's decimated immune system.
Efforts to grow human hematopoietic stem cells in the
laboratory have proven extraordinarily difficult, Chute said,
because growth factors in culture make stem cells rapidly
differentiate. The scientists searched for ways to block a stem
cell's natural propensity to differentiate without promoting
The researchers focused on the ALDH enzyme because it is a
telltale "marker" that distinguishes stem cells from other
blood and immune cells. Moreover, it is known to play an
essential role in the body's production of retinoic acids,
which regulate cell differentiation in a variety of tissues.
Yet how ALDH functions in stem cells remained unknown, Chute
The scientists began by analyzing how stem cells behave
under normal circumstances when grown in culture. They mixed
together purified human stem cells with growth factors that
induce stem cells to mature and differentiate. As expected, the
stem cells showed a marked decline in number as they
differentiated into other types of specialized cells. By day
seven, all stem cells had disappeared from culture.
The scientists then added an inhibitor of ALDH to the stem
cell cultures, and they found that half of the stem cells
maintained their immature and undifferentiated status.
Moreover, adding the inhibitor caused a 3.4-fold increase in
stem cell numbers within seven days.
Next, the scientists transplanted the cultured stem cells into
immune-deficient mice to determine how the stem cells would
behave. The new population of stem cells migrated to the bone
marrow as expected and successfully "engrafted," or took hold
in the bone marrow, where they began to produce new blood and
"ALDH appears to play a fundamental role in the
differentiation program of human hematopoietic stem cells,"
Chute said. "Inhibition of this enzyme facilitates the
expansion of human hematopoietic stem cells in culture."
Chute said their results reveal a unique role for both ALDH and
the process of retinoic acid signaling in human stem cells.
Chute and colleague Donald McDonnell, Ph.D., professor of
pharmacology and cancer biology, are currently testing whether
they can directly block the retinoic acid receptors in stem
cells and produce a comparable expansion of human stem
The investigators plan to develop a clinical trial to test
their approach to expand human stem cells for therapeutic