Blood cells in the right place at the right time

Just like in any good murder mystery, information about where and when hematopoietic stem cells (HSCs) originate should give us clues about their function. HSCs eventually differentiate into blood cells but start off in the aorta, and researchers wondered why. In the developing embryo, these cells do not differentiate into blood cells until circulation is established. Scientists wondered about this too.

New research from Dr. George Daley at the Harvard Stem Cell Institute suggests that the physical forces exerted by a heartbeat and the blood flow that results trigger the formation of new blood cells.¹ He found that mechanical forces can also regulate pathways that lead to differentiation.² Before this discovery, scientists thought blood cell differentiation was primarily controlled by cell-to-cell signaling.

Dr. Daley performed a systematic evaluation to determine whether mechanical forces were the reason why HSCs originate in the aorta and wait for a pulsating bloodstream before they commit to differentiation. His group screened 2500 chemicals for their effect on hematopoietic stem cell production in zebrafish embryos. Amazingly, the researchers found a direct effect between a chemical's effect on blood flow and the number of HSCs in the aorta. Drugs that increased pressure also increased the number of stem cells.

For the perfect experiment, scientists would need to take a bloodstream without a heartbeat and show that when they introduced a pulse, they were able to increase the number of hematopoietic stem cells. A zebrafish with a mutation called silent heart (sih) provided a great model system. This zebrafish never develops a heartbeat, and exhibits lower expression levels of known blood stem cell markers. When scientists treated these embryos with a compound that increased blood flow, they also observed elevated numbers of HSCs.

Interestingly, the group observed the same phenomenon in the mammalian system, through experiments on mouse embryonic stem cells. The researchers propelled fluid over the cultured cells to simulate shear stress, the force that results from the friction between blood and the endothelial cells that make up the vessel wall. The results confirmed that mechanical forces such as shear stress lead to blood cell development.

What's the underlying mechanism? Nitric oxide (NO) is important in the process.³ It's a safe bet, since NO plays a role in a huge variety of chemical reactions. Furthermore, NO has been shown to affect the generation of hematopoietic stem cells. The compound may convert the physical forces of blood flow into chemical signals that lead to differentiation. NO even restored the phenotype of silent heart embryos to that of wild-type zebrafish.

The research has far-reaching implications. If the location and timing of HSC activity are this important, we may observe the same trends in other aspects of embryonic pattern formation. This exciting new information also brings scientists one step closer to generating blood stem cells in the lab.

¹Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature. 13 May 2009.
²Akst, J. Blood grows when it flows. The Scientist. 13 May 2009.
³North, T., et al. Hematopoietic Stem Cell Development Is Dependent on Blood Flow. Cell. 14 May 2009.