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

Miguel F. Diaz, Nan Li, Hyun Jung Lee, Luigi Adamo, Siobahn M. Evans, Hannah E. Willey, Natasha Arora, Yu suke Torisawa, Dwayne A. Vickers, Samantha A. Morris, Olaia Naveiras, Shashi K. Murthy, Donald E. Ingber, George Q. Daley, Guillermo García-Cardeña, Pamela L. Wenzel

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)665-680
Number of pages16
JournalJournal of Experimental Medicine
Volume212
Issue number5
DOIs
StatePublished - May 4 2015
Externally publishedYes

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    Diaz, M. F., Li, N., Lee, H. J., Adamo, L., Evans, S. M., Willey, H. E., Arora, N., Torisawa, Y. S., Vickers, D. A., Morris, S. A., Naveiras, O., Murthy, S. K., Ingber, D. E., Daley, G. Q., García-Cardeña, G., & Wenzel, P. L. (2015). Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. Journal of Experimental Medicine, 212(5), 665-680. https://doi.org/10.1084/jem.20142235