Scientists Grow Blood-Producing Stem Cells Outside The Body

Blood stem cells are solely responsible for the ability to regrow the blood cell system after intense chemotherapy or irradiation.

One reason that it's important to be able to grow stem cells in a laboratory is because they are rare, and large numbers of stem cells must be transplanted in order for the transplant to be successful. Only one in every 100,000 bone marrow cells is a stem cell that can produce blood.

Until now, blood stem cells could not be multiplied outside the body. In fact, under the best known culture conditions, essentially all blood stem cells normally died off after one month outside of the body.

But by using a new growth hormone and optimizing cell culture conditions, UW scientists have actually generated large numbers of mouse blood stem cells in the laboratory and maintained them for up to four months.

The presence of the blood stem cells was proven by transplanting the cultured cells into lethally irradiated mice. The cultured stem cells were able to "rescue" the mice by providing a new blood cell system.

"It's now almost a year later, and these animals are walking around as healthy as they can possibly be. We can't find anything wrong with them," says Dr. Stephen Bartelmez, assistant professor of pathobiology at the UW School of Public Health and Community Medicine, and a principal investigator at the Seattle Biomedical Research Institute. "The implications of this are huge."

This is the first time that blood-producing, or hematopoietic, stem cells have survived and reproduced successfully outside a body for any length of time, Bartelmez says. "It was the first demonstration that stem cells could be substantially expanded outside of an animal," he said.

Bartelmez is principal author of the study, which will be published July 6 in the Proceedings of the National Academy of Sciences. The discovery was made possible by close collaboration with Dr. Gerald Roth, professor of medicine (hematology) at the UW and chief of hematology at the Veterans Administration Medical Center in Seattle, and Dr. Mayumi Yagi, research assistant professor of medicine (hematology) at the UW.

The project had its roots in lab work that Yagi was doing at the VA involving TPO, or thrombopoietin (pronounced throm-bow-PO-it-in), a hormone discovered in 1994 by a Seattle-based team that included UW scientists.

Yagi and Roth's experiments involved encouraging platelet growth outside of the body. Bartelmez, an expert on stem cells, looked at the cultures and saw cells that looked like blood stem cells flourishing after several months in the VA laboratory.

"I looked at this culture, and I just about fell over. It was totally unheard of," Bartelmez says.

The team duplicated those results in the SBRI lab, and the Bartelmez lab began intensive study to demonstrate the presence of the stem cells in the cultures, determine if the stem cells were actually being generated in the culture and study the mechanism behind the stem cell expansion.

The discovery may allow better care of cancer patients when this method is translated into human usage, Bartelmez says. Chemotherapy and radiation treatments kill cancer, but they also kill healthy blood cells in the bone marrow.

Since their bone marrow is no longer producing blood cells, cancer patients may suffer from infections, fatigue and bleeding.

"Using the new method, doctors might remove stem cells from a patient, and multiply them in the laboratory while the patient is receiving chemotherapy," Bartelmez says.

The discovery will also have implications for genetic research and treatment, Bartelmez says. The use of TPO cultures may allow scientists to introduce normal genes into the stem cells of patients suffering from diseases known to be caused by single mutated (abnormal) genes, and then multiply these "improved" stem cells. The newly engineered blood stem cells will then carry the corrected gene indefinitely.

"If we can insert a normal gene into these dividing stem cells, we may in many cases cure the disease," Bartelmez says. "One reason nobody has been able to do this up until now is because no one can get stem cells to divide outside the animal and just keep dividing. This discovery may be an important step for gene therapy to become a practical reality."

As a next step, the UW scientists plan to begin studying this blood stem cell multiplication technique in baboons. Human culture studies are under way. If these studies are successful, trials in humans may follow.

One reason the connection between stem cell growth and TPO has gone undiscovered is that a complex mix of cells appears to drive the stem cell expansion, and substantial time is required to allow the TPO cultures to develop. Bartelmez says that the stem cells did not begin to multiply until after one month in culture. Most previous studies were not continued so long.

The 23-year-old Seattle Biomedical Research Institute is a nonprofit organization that conducts research in molecular pathogenesis - the interactions of disease at a subcellular level - with a goal of improving worldwide health. It is affiliated to the UW's School of Public Health and Community Medicine through faculty and students who conduct research there. SBRI's director, Dr. Kenneth D. Stuart, is chairman of the UW Department of Pathobiology.