For blood stem cells, the force is strong

Blood stem cells grow with the flow, two new studies show.

The 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 discovery 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 children and adults, blood stem cells reside in the bone marrow. Only about a third of patients who require 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 Program at Children’s Hospital Boston, and a coauthor of one of the new studies, which appears online May 13 and in the May 15 Cell.

Scientists can make red and white blood cells easily in the laboratory, but bone marrow patients need blood stem cells to constantly replenish their blood supply. Producing these cells, also called hematopoietic stem cells, is 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 nitric oxide plays an important role.

Daley’s group directly tested the ability of blood flow to turn 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 in development, 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 that were exposed to a different magnitude of shear stress, such as that in the human aorta, did not.

A nitric oxide–blocking drug reduced the number of blood stem cells induced by the shear stress. Nitric oxide is a chemical produced naturally in the body and is known to be important in regulating blood vessel growth and elasticity.

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

Zon’s team used zebrafish embryos, which are transparent, to watch the stem cells develop. He and his colleagues found that chemicals that increase blood flow in the tails of zebrafish embryos also boost activity of the RUNX1 gene, a master regulator of blood stem cells. Mutant embryos that don’t have a heartbeat because of a defect in a heart muscle protein don’t make hematopoietic stem cells in their tails.

When the researchers gave a nitric oxide compound to the mutant embryos, however, the embryos produced more blood stem cells. The nitric oxide–blocker also 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.

Intuitively, scientists might expect that mechanical forces play a role in shaping development, but few biologists have studied this due to experimental difficulties, says Ihor Lemischka, a stem cell biologist at Mount Sinai School of Medicine in New York City.

“I think we’ll be seeing more of these types of studies,” Lemischka says.

It’s still not clear how the cells sense shear stress, and researchers are trying to unravel the chain of events between mechanical force and stem cell production in order to manipulate the process to make blood stem cells for transplant.