Here’s some exciting news regarding hematopoietic stem cell development coming from Boston (The Pluripotent headquarters). Two studies by Leonard Zon’s and George Daley’s groups have supported the following hypothesis: A beating heart and blood flow are necessary for development of the blood system, which relies on mechanical stresses to cue its formation.
Zon and colleagues found that compounds that modulate blood flow had a potent impact on the expression of a Runx1, a master regulator of blood formation. Runx1 is also a recognized marker for the blood stem cells that give rise to all the cell types in the blood system. They also observed that a strain of mutant embryos that lacked a heartbeat and blood circulation exhibited severely reduced numbers of blood stem cells. And the key biochemical regulator that was in charge of all this? Nitric oxide! Increasing nitric oxide in the blood of mutant embryos rescued blood stem cell production.
Daley and colleagues discovered that just the stress and biomechanical forces on the lining of blood vessels were able to increase the production of progenitor cells that gave rise to blood cells.
The report by Children’s Hospital says “the authors of the two papers speculate that drugs that mimic the effects of embryonic blood flow on blood precursor cells, or molecules involved in nitric oxide signaling, might be therapeutically beneficial for patients with blood diseases. For example, nitric oxide could be used to grow and expand blood stem cells either in the culture dish or in patients after transplantation.”
Anyone up for testing nitric oxide for blood doping? On second thought, please don’t try it.
During vertebrate embryogenesis, hematopoietic stem cells (HSCs) arise in the aorta-gonads-mesonephros (AGM) region. We report here that blood flow is a conserved regulator of HSC formation. In zebrafish, chemical blood flow modulators regulated HSC development, and silent heart (sih) embryos, lacking a heartbeat and blood circulation, exhibited severely reduced HSCs. Flow-modifying compounds primarily affected HSC induction after the onset of heartbeat; however, nitric oxide (NO) donors regulated HSC number even when treatment occurred before the initiation of circulation, and rescued HSCs in sih mutants. Morpholino knockdown of nos1 (nnos/enos) blocked HSC development, and its requirement was shown to be cell autonomous. In the mouse, Nos3 (eNos) was expressed in HSCs in the AGM. Intrauterine Nos inhibition or embryonic Nos3 deficiency resulted in a reduction of hematopoietic clusters and transplantable murine HSCs. This work links blood flow to AGM hematopoiesis and identifies NO as a conserved downstream regulator of HSC development.
Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system1, 2. After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3–5), a master regulator of haematopoiesis, and give rise to haematopoietic cells4. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential6. Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41+c-Kit+ haematopoietic progenitor cells7, concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta–gonads–mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling8, compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development.
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