Here’s a highlight for research published in Cell and Nature:
Beating heart triggers blood stem cells in the embryo
Embryonic haematopoiesis needs flow, nitric oxide signalling
Blood stem cells are born just outside the embryonic heart. Though this fact is well known, the reasons behind it have posed a persistent mystery. Now two strands of research, one starting with embryonic stem cells, another with zebrafish, provide big clues. The solution may help researchers create a useful but elusive cell — the haematopoietic stem cells capable of replenishing an entire blood system.
The work, led by two teams of researchers from Harvard University, shows that haematopoietic stem cells form best under stress — more specifically, under the strain exerted by moving fluid, the flow created by a beating heart.
Researchers led by Leonard Zon studied zebrafish embryos with a mutation called silent heart, which prevents the zebrafish from developing a heartbeat. Zon showed that the clusters from which haematopoietic stem cells should arise seemed stunted. Zon and his colleagues screened the fish embryos with small molecules affecting various pathways. “Most of those chemicals required circulation to be in place for it to increase stem cells,” says Zon, but chemicals that generated nitric oxide signalling worked even without blood flow and could even restore the stunted clusters. Satisfyingly, the observation also held true in mouse embryos: blood stem cells in the embryonic aorta (the aorta-gonad-mesonephros region or AGM) expressed an enzyme that produces nitric oxide. Furthermore, shutting down the nitric oxide signalling pathway decreased the number of haematopoietic clusters.
Researchers led by Guillermo García-Cardeña and George Daley found the same solution by a different approach: they cultured mouse embryonic stem cells under conditions designed to mimic the fluid shear stress caused by flow in the AGM. (Doing so required them to miniaturize a flow chamber for studying blood vessel formation so that it could function at the level of a 96-well plate.) Compared with cells grown in static conditions, cells in a flow had higher levels of CD31 and Runx1, proteins associated with blood formation. Additionally, compared with cells grown in static conditions, cell exposed to shear stress created more haematopoietic colony–forming units. Again, the effect seemed to be mediated by nitric oxide signalling. Fewer colonies were produced by cells grown under cell stress if nitric oxide production was inhibited (with a nitric oxide synthase inhibitor called nitro-L-arginine methyl ester). Next, the team studied mouse embryos genetically engineered to lack both a heart beat and blood flow. When these embryos were exposed to fluid shear stress, embryonic sites of blood formation began to express Runx1, a master regulator of blood formation.
Not only does this work help unravel a tangled biological question, but also it suggests that the nitric oxide signal could be used to convert embryonic stem cells to blood stem cells, a much sought-after goal. “It’s not entirely clear that nitric oxide is the only story,” says Daley, but “we know it is one of the pathways.”
1. North, T. E. et al. Hematopoietic stem cell development is dependent on blood flow. Cell 137, 736–748 (2009).
2. Adamo, L. et al. Biomechanical forces promote embryonic hematopoiesis. Nature advance online publication, doi:10.1038/nature08073 (13 May 2009).