June 1, 2009

Flow Forces Promote Embryonic Blood Cell Formation

Image of a colony of red blood cells A red blood cell colony emerges from embryonic cells in response to fluid flow. Luigi Adamo and Guillermo Garcia-Cardena.

Researchers have discovered that cells in an embryo are prompted to develop into blood cells by the force of rushing fluid being pushed by the beating heart. The finding has important implications for developing stem cell therapies for blood diseases.

A major research challenge is to learn how to guide embryonic stem cells to give rise to blood-forming stem cells, and then ultimately to produce all the different types of blood cells in the body, including red blood cells and the cells of the immune system. Scientists already knew that, in the developing mouse embryo, blood-forming stem cells initially arise in the primitive circulatory system after the heartbeat begins. That's about when the gene Runx1, a master regulator of blood cell development, becomes activated in the cells that line the blood vessels.

A research team led by Drs. Luigi Adamo, Olaia Naveiras, Guillermo García-Cardeña and George Q. Daley suspected that the shear stress of fluid driven by the heart and being pushed past these cells may play a role in the creation of new blood cells. In fact, the forces created by blood flow within the developing heart are already known to play a significant role in how the heart forms. With funding from NIH, the team of investigators—affiliated with Harvard, other research institutions in Boston and Indiana University—searched for a connection between biomechanical force and blood cell development.

The scientists first estimated the shear stress acting on cells that line the inner surface of the mouse aorta once the embryo's heart begins beating. The aorta originates at the heart and is the largest blood vessel in the body. The researchers then put mouse embryonic stem cells, developed to the early stages of blood cell development, onto a flat surface. Next they flowed fluid over the surface to match the shear stress experienced by the cells lining the mouse aorta.

In the online edition of Nature on May 13, 2009, the scientists reported that, compared to cells grown under static conditions, cells exposed to fluid stress expressed higher levels of Runx1 and other genes associated with blood cell development. The cells exposed to shear stress also formed more of the cell colonies that give rise to blood cells, a sign they were differentiating into more mature cells.

The scientists next tested whether nitric oxide (NO) is involved in the process. NO is a signaling molecule known to be produced by certain cells exposed to shear stress. It also plays a role in blood cell development. Adding a compound that inhibits NO production diminished the formation of cell colonies under shear stress, but it had no effect on static cells. Notably, the inhibitor didn't affect Runx1 levels, showing that NO production comes after Runx1 in the molecular pathway leading to blood cell development.

Similar experiments with cells taken from mouse embryos further supported the idea that biomechanical forces help stimulate the development of blood cells.

“In learning how the heartbeat stimulates blood formation in embryos, we've taken a leap forward in understanding how to direct blood formation from embryonic stem cells in the petri dish,” says Daley. Future efforts to coax stem cells into blood cells for research or therapies will need to consider the effects of biomechanical forces on cell fate.

—by Harrison Wein, Ph.D.

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