Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis

Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. Here we show that fluid shear stress endows long-term multilineage engraftment potential...

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Bibliographic Details
Published in:The Journal of experimental medicine 2015-05, Vol.212 (5), p.665-680
Main Authors: Diaz, Miguel F, Li, Nan, Lee, Hyun Jung, Adamo, Luigi, Evans, Siobahn M, Willey, Hannah E, Arora, Natasha, Torisawa, Yu-Suke, Vickers, Dwayne A, Morris, Samantha A, Naveiras, Olaia, Murthy, Shashi K, Ingber, Donald E, Daley, George Q, García-Cardeña, Guillermo, Wenzel, Pamela L
Format: Article
Language:English
Subjects:
Animals
Blood Flow Velocity
Cyclic AMP - genetics
Cyclic AMP - metabolism
Cyclic AMP Response Element-Binding Protein - genetics
Cyclic AMP Response Element-Binding Protein - metabolism
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
Dinoprostone - genetics
Dinoprostone - metabolism
Embryo, Mammalian - cytology
Embryo, Mammalian - embryology
Mesonephros - blood supply
Mesonephros - cytology
Mesonephros - embryology
Mice
Mice, Knockout
Signal Transduction - physiology
Stress, Physiological - physiology
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Summary:Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. Here we show that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at embryonic day 9.5, an embryonic stage not previously described to harbor HSCs. Effects on hematopoiesis are mediated in part by a cascade downstream of wall shear stress that involves calcium efflux and stimulation of the prostaglandin E2 (PGE2)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling axis. Blockade of the PGE2-cAMP-PKA pathway in the aorta-gonad-mesonephros (AGM) abolished enhancement in hematopoietic activity. Furthermore, Ncx1 heartbeat mutants, as well as static cultures of AGM, exhibit lower levels of expression of prostaglandin synthases and reduced phosphorylation of the cAMP response element-binding protein (CREB). Similar to flow-exposed cultures, transient treatment of AGM with the synthetic analogue 16,16-dimethyl-PGE2 stimulates more robust engraftment of adult recipients and greater lymphoid reconstitution. These data provide one mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20142235