Stem Cell Savvy

Researchers look to genes for clues as they seek ways to convince stem cells to make more of their own.

By Mary Hoff

Produce or reproduce? That is the question hematopoietic stem cells (HSCs) face every time they divide. These multitalented cells, found in bone marrow and umbilical cord blood, produce all 10 types of blood cells that cruise our circulatory system, carrying oxygen and fighting infections. They also, on occasion, put that job on hold to make more of their own kind, a process known as self-renewal. What determines which task they tackle at a particular time?

Scientists led by Stem Cell Institute Director Catherine Verfaillie are working hard to figure that out—and for good cause. Treatment of leukemia and other blood disorders often involves wiping out a patient’s own faulty HSCs— essentially, firing all the workers in the factory—and replacing them with healthy new ones harvested from donors. But it’s hard to muster replacement workers in healing quantities.

“There are a limited number of stem cells we can get from an umbilical cord, insufficient to transplant into a larger patient,” says research team member Craig Eckfeldt. “If we can determine what types of genes or signaling pathways [a hematopoietic stem cell] uses to selectively renew itself, then we can try to develop conditions in the laboratory to recapitulate that process.”

Recently Eckfeldt, Verfaillie, and colleagues announced a major step toward this goal. Using a process called transcript microarray technology, which allows researchers to identify which genes are active in a particular cell at a particular moment in time, the team found 61 genes that differ between stem cells and more mature cells and were not already known to be involved in bloodcell development.

Next, they set out to determine whether those genes really develop blood cells. They used zebrafish, which are ideal for this work because they reproduce rapidly and make new blood cells in much the same way humans do. They observed what happened —more accurately, what didn’t happen— when they blocked the activity of those genes one at a time. This innovative approach, which Eckfeldt refers to as a “high-throughput functional genomics screen,” produced a list of 14 specific genes that are clearly involved in the process of making new blood cells.

“It’s given us a starting point for figuring out if we can manipulate this self-renewal process,” Eckfeldt says. The next step, he says, is to go back to mouse or human cells to see if the zebrafish findings hold true in mammals as well. “If we’re lucky, we’ll be able to take this all the way through and ultimately change the course of how we go about collecting and treating hematopoietic stem cells for transplantation.”

In addition to yielding valuable information about the genetic basis for blood cell production and HSC self-renewal, the study also paves the way for future advances by demonstrating a valuable new research technique. The high-throughput screening, Eckfeldt says, could be applied to research to improve understanding of development of other systems, including the circulatory system, pancreas, and heart.

“There’s definitely a potential to discover what types of genes might be important not just for the development of organs…but also the regeneration of organs when they’re damaged,” he says. “It’s really exciting because there are so many potential applications. I really do think this is one of the major next steps in trying to unlock the potential of stem cells.”

What are stem cells? Stem cells are parent cells for all parts of the body. They maintain and repair cells in the areas where they are found. Stem cells are found in the blood, bone marrow, skin, muscle, and organs like the brain and liver. Scientists work with different kinds of stem cells: animal and human, embryonic stem cells, and adult stem cells. For more information, see the Web site for the Stem Cell Institute www.stemcell.umn.edu.