The beating heart of an embryo is one of the first detectable organs, forming long before the embryo requires a functional circulatory system for delivery of nutrients and removal of waste products. North et al. provide evidence that the beating heart and flow through the developing circulatory system is necessary for the development of hematopoietic stem cells (HSCs), which produce all of the types of blood cells, both during embryogenesis and during adulthood. In a chemical screen for compounds that altered the abundance of HSCs in zebrafish embryos, the authors noted a correlation between compounds that changed blood flow and HSC number: Compounds that increased blood flow, triggering vessel dilation, increased the number of HSCs, and compounds that decreased flow, triggering vessel constriction, decreased the number of HSCs. Furthermore, zebrafish with a mutation in the gene silent heart (sih) lack a heartbeat and also showed impaired specification of arteries and a dramatic reduction in HSCs. Chemicals that triggered the formation of nitric oxide (NO) were the only compounds that could be applied before the onset of the heartbeat that could promote HSC formation. Chemicals that inhibit NO decreased HSC formation even when applied before the onset of the heartbeat and also prevented the increase in HSC formation in response to compounds that stimulated blood flow. Exposure of zebrafish embryos to SNAP, a compound that produces NO, rescued HSC formation in the sih mutants, suggesting that blood flow acts through NO to stimulate HSC formation. Zebrafish have two nitric oxide synthase (NOS) genes, nos1 (related to mammalian neuronal NOS and endothelial NOS) and nos2 (inducible NOS). Knockdown of nos1, but not nos2, decreased HSC formation. Furthermore, compounds that stimulated blood flow and HSC formation increased the expression of nos1, and nos1 expression was reduced in the sih mutants. Experiments in mice suggested that the connection between NO and HSC formation was conserved. These data regarding HSCs and NO expand the functions of NO in the developing circulatory system, which is also important for vessel formation and tone.
T. E. North, W. Goessling, M. Peeters, P. Li, C. Ceol, A. M. Lord, G. J. Weber, J. Harris, C. C. Cutting, P. Huang, E. Dzierzak, L. I. Zon, Hematopoietic stem cell development is dependent on blood flow. Cell 137, 736–748 (2009). [PubMed]