Duke scientists find way to grow stem cells in laboratory
Scientists at Duke Medical Center demonstrated they could grow human stem cells in the laboratory by blocking an enzyme that naturally triggers them 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, according to the researchers.
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 blood 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 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 will be published in the Aug. 1 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 Dr. John Chute, 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 bone marrow cells. Likewise, cord blood frequently lacks sufficient numbers of stem cells to rebuild a patient's decimated immune system.
Efforts to grow human blood stem cells in the laboratory have proven extraordinarily difficult, Chute said, because growth factors in cultures make stem cells rapidly differentiate. The scientists searched for ways to block a stem cell's natural propensity to differentiate without promoting uncontrolled growth.
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 said.
"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 the Duke researchers' results revealed a unique role for both ALDH and the process of retinoic acid signaling in human stem cells. Chute and colleague Donald McDonnell, 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 cells.
The investigators plan to develop a clinical trial to test their approach.
