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Going with the flow: how shear stress signals the emergence of adult hematopoiesis.

Traver D - J. Exp. Med. (2015)

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California, San Diego.

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In this issue, three companion papers demonstrate that this is not just a coincidence and describe a mechanism by which the shear stress of blood flow triggers a cascade of molecular events leading to the birth of hematopoietic stem cells (HSCs)... Jing et al. show that binding of adenosine to the A2b adenylyl cyclase-stimulatory receptor on vascular endothelium leads to up-regulation of the cAMP–PKA–CREB pathway to activate the CXCL8 cytokine gene, which is in turn required for HSC development... Kim et al. show that flow-induced cAMP–PKA–CREB signaling also leads to secretion of bone morphogenetic proteins (BMPs) to promote HSC emergence... These authors suggest that CREB function leads to production and secretion of BMP2 and BMP4, which bind to type I BMP receptors on hemogenic endothelium to promote EHT... Finally, Diaz et al. demonstrate that blood flow promotes the synthesis and release of prostaglandin E2 (PGE2) by vascular endothelium... This also leads to stimulation of the cAMP–PKA–CREB signaling axis via the EP2/EP4 receptors to activate several master regulators of the hematopoietic program... Importantly, these authors show that provision of flow conditions to cultured E9.5 murine tissues that normally lack HSC activity confers long-term, multilineage engraftment potential... That ectopic provision of flow conditions or PGE2 analogues can confer precocious HSC potential to cultured precursors suggests that this strategy could help in vitro efforts to instruct HSC fate from human pluripotent cells... Despite decades of efforts, this feat has not yet been achieved... Collectively, these studies suggest that exposing cultured cells to flow, or experimentally modulating the cAMP–PKA–CREB signaling pathway, may be a key step toward achieving this important milestone of regenerative medicine.

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Model of flow-induced signal transduction events. Shear force induces signaling events that are orchestrated by the cAMP–PKA–CREB pathway to produce PGE2, adenosine, and BMP, which drive HSC production.
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fig2: Model of flow-induced signal transduction events. Shear force induces signaling events that are orchestrated by the cAMP–PKA–CREB pathway to produce PGE2, adenosine, and BMP, which drive HSC production.


Going with the flow: how shear stress signals the emergence of adult hematopoiesis.

Traver D - J. Exp. Med. (2015)

Model of flow-induced signal transduction events. Shear force induces signaling events that are orchestrated by the cAMP–PKA–CREB pathway to produce PGE2, adenosine, and BMP, which drive HSC production.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4419338&req=5

fig2: Model of flow-induced signal transduction events. Shear force induces signaling events that are orchestrated by the cAMP–PKA–CREB pathway to produce PGE2, adenosine, and BMP, which drive HSC production.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California, San Diego.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In this issue, three companion papers demonstrate that this is not just a coincidence and describe a mechanism by which the shear stress of blood flow triggers a cascade of molecular events leading to the birth of hematopoietic stem cells (HSCs)... Jing et al. show that binding of adenosine to the A2b adenylyl cyclase-stimulatory receptor on vascular endothelium leads to up-regulation of the cAMP–PKA–CREB pathway to activate the CXCL8 cytokine gene, which is in turn required for HSC development... Kim et al. show that flow-induced cAMP–PKA–CREB signaling also leads to secretion of bone morphogenetic proteins (BMPs) to promote HSC emergence... These authors suggest that CREB function leads to production and secretion of BMP2 and BMP4, which bind to type I BMP receptors on hemogenic endothelium to promote EHT... Finally, Diaz et al. demonstrate that blood flow promotes the synthesis and release of prostaglandin E2 (PGE2) by vascular endothelium... This also leads to stimulation of the cAMP–PKA–CREB signaling axis via the EP2/EP4 receptors to activate several master regulators of the hematopoietic program... Importantly, these authors show that provision of flow conditions to cultured E9.5 murine tissues that normally lack HSC activity confers long-term, multilineage engraftment potential... That ectopic provision of flow conditions or PGE2 analogues can confer precocious HSC potential to cultured precursors suggests that this strategy could help in vitro efforts to instruct HSC fate from human pluripotent cells... Despite decades of efforts, this feat has not yet been achieved... Collectively, these studies suggest that exposing cultured cells to flow, or experimentally modulating the cAMP–PKA–CREB signaling pathway, may be a key step toward achieving this important milestone of regenerative medicine.

Show MeSH