Force is strong for blood stem cells, at least in mice, zebrafish embryos: studies show blood flow and nitric oxide boost production.

Blood stem cells grow with the flow.

Two new studies, led by independent groups at Children's Hospital Boston, report that an embryo's heartbeat and blood circulation stimulate the growth of blood stem cells.

The find could be a boon to researchers seeking to make blood stem cells for people with blood cancers, immune system disorders and other diseases that require bone marrow transplants. In people, blood stem cells reside in the bone marrow and constantly replenish blood supply. Only about a third of patients who need bone marrow transplants have matching donors.

"Basically we cannot offer optimal therapy to two-thirds of patients," says Leonard Zon, director of the Stem Cell Research Program at Children's Hospital Boston and a coauthor of one of the new studies, appearing in the May 15 Cell.

Scientists can make red and white blood cells from embryonic stem cells easily in the laboratory, but producing blood stem cells, called hematopoietic stem cells, has been much more difficult, Zon says. Now, his group suggests that a little force can boost blood stem cell production in zebrafish embryos.

Reporting online May 13 in Nature, a group led by George Daley, director of the Pediatric Stem Cell Transplantation Program at Children's Hospital Boston, demonstrates that blood flow also triggers hematopoietic stem cell production in mouse embryos. Both groups found that nitric oxide plays a role.

Intuitively, scientists might expect that mechanical forces help shape development. But because of experimental difficulties, few biologists have studied this, says Ihor Lemischka of Mount Sinai School of Medicine in New York City. "I think we'll be seeing more of these types of studies," Lemischka says.

Daley's group directly tested the ability of blood flow to turn embryonic stem cells into hematopoietic stem cells. The team placed mouse embryonic stem cells in a centrifuge-like device that mimics shear stress--the frictional force blood creates when it flows over cells--in a mouse's aorta. In early embryos, blood stem cells first form on the floor of the aorta. Later they migrate to the bone marrow.

Embryonic stem cells exposed to the same magnitude of shear stress as found in the mouse aorta produced hematopoietic stem cells. Cells exposed to a different magnitude of stress didn't. A nitric oxide--blocking drug reduced the number of blood stem cells that stress induced. Nitric oxide is a chemical produced naturally in the body that helps regulate blood vessel growth and elasticity.

When the researchers gave the nitric oxide blocker to pregnant mice, mouse embryos also had problems making blood stem cells.

Zon's team used zebrafish embryos, which are transparent, to watch the stem cells develop. The team found that chemicals that increase blood flow in the tails of the embryos also boost activity of the RUNX1 gene, a master regulator of blood stem cells. Mutant embryos that don't have a heartbeat don't make many hematopoietic stem cells in their tails.

When the researchers gave a nitric oxide-boosting compound to the mutant embryos, however, the embryos produced more blood stem cells. And the nitric oxide blocker inhibited blood stem cell production, the researchers found. Those findings suggest that blood flow may increase nitric oxide levels, which then boost stem cell production, Zon says.