Cardiovascular Research

Biomechanical forces promote embryonic haematopoiesis.

Authors: Luigi Adamo|||Olaia Naveiras|||Pamela L Wenzel|||Shannon McKinney-Freeman|||Peter J Mack|||Jorge Gracia-Sancho|||Astrid Suchy-Dicey|||Momoko Yoshimoto|||M William Lensch|||Mervin C Yoder|||Guillermo García-Cardeña|||George Q Daley

Affiliations: + Expand

Abstract

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. 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 cells. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential. 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 cells, 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 signalling, 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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Chemical List

Core Binding Factor Alpha 2 Subunit|||Endothelium-Dependent Relaxing Factors|||Runx1 protein, mouse|||Nitric Oxide

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Reference List

Hove JR, et al. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature. 2003;421:172–177.|||Lucitti JL, et al. Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development. 2007;134:3317–3326.|||Garcia-Porrero JA, Godin IE, Dieterlen-Lievre F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat. Embryol. 1995;192:425–435.|||North TE, et al. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity. 2002;16:661–672.|||Rhodes KE, et al. The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell. 2008;2:252–263.|||Lensch MW, Daley GQ. Origins of mammalian hematopoiesis: in vivo paradigms and in vitro models. Curr. Top. Dev. Biol. 2004;60:127–196.|||Mikkola HK, Fujiwara Y, Schlaeger TM, Traver D, Orkin SH. Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood. 2003;101:508–516.|||Garcia-Cardena G, et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature. 1998;392:821–824.|||Haar JL, Ackerman GA. A phase and electron microscopic study of vasculogenesis and erythropoiesis in the yolk sac of the mouse. Anat. Rec. 1971;170:199–223.|||Ji RP, et al. Onset of cardiac function during early mouse embryogenesis coincides with entry of primitive erythroblasts into the embryo proper. Circ. Res. 2003;92:133–135.|||Tavian M, et al. The vascular wall as a source of stem cells. Ann. NY Acad. Sci. 2005;1044:41–50.|||Garin G, Berk BC. Flow-mediated signaling modulates endothelial cell phenotype. Endothelium. 2006;13:375–384.|||Kabrun N, et al. Flk-1 expression defines a population of early embryonic hematopoietic precursors. Development. 1997;124:2039–2048.|||Lengerke C, et al. BMP and WNT specify hematopoietic fate by activation of the CDX-Hox pathway. Cell Stem Cell. 2008;2:72–82.|||Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell. 1996;86:897–906.|||Cumano A, Dieterlen-Lievre F, Godin I. Lymphoid potential, probed before circulation in mouse, is restricted to caudal intraembryonic splanchnopleura. Cell. 1996;86:907–916.|||Phoon CK, Aristizabal O, Turnbull DH. Spatial velocity profile in mouse embryonic aorta and Doppler-derived volumetric flow: a preliminary model. Am. J. Physiol. Heart Circ. Physiol. 2002;283:H908–H916.|||Ku D. Blood flow in arteries. Annu. Rev. Fluid Mech. 1997;29:399–434.|||Yamamoto K, et al. Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. Am. J. Physiol. Heart Circ. Physiol. 2005;288:H1915–H1924.|||Basu P, et al. KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo. Blood. 2005;106:2566–2571.|||Parmar KM, et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J. Clin. Invest. 2006;116:49–58.|||Wang Y, Yates F, Naveiras O, Ernst P, Daley GQ. Embryonic stem cell-derived hematopoietic stem cells. Proc. Natl Acad. Sci. USA. 2005;102:19081–19086.|||Aicher A, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nature Med. 2003;9:1370–1376.|||Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc. Natl Acad. Sci. USA. 1989;86:3375–3378.|||Ferkowicz MJ, et al. CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo. Development. 2003;130:4393–4403.|||Koushik SV, et al. Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J. 2001;15:1209–1211.|||Lux CT, et al. All primitive and definitive hematopoietic progenitor cells emerging prior to E10 in the mouse embryo are products of the yolk sac. Blood. 2007;111:3435–3438.|||Simeone A, Daga A, Calabi F. Expression of runt in the mouse embryo. Dev. Dyn. 1995;203:61–70.|||North T, et al. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development. 1999;126:2563–2575.|||Jones EA, Baron MH, Fraser SE, Dickinson ME. Measuring hemodynamic changes during mammalian development. Am. J. Physiol. Heart Circ. Physiol. 2004;287:H1561–H1569.|||Ji RP, et al. Onset of cardiac function during early mouse embryogenesis coincides with entry of primitive erythroblasts into the embryo proper. Circ. Res. 2003;92:133–135.|||Phoon CK, Aristizabal O, Turnbull DH. Spatial velocity profile in mouse embryonic aorta and Doppler-derived volumetric flow: a preliminary model. Am. J. Physiol. Heart Circ. Physiol. 2002;283:H908–H916.|||Jones EA, Baron MH, Fraser SE, Dickinson ME. Measuring hemodynamic changes during mammalian development. Am. J. Physiol. Heart Circ. Physiol. 2004;287:H1561–H1569.|||Nosek TM. Essentials of Human physiology — Cardiac and Circulatory Physiology. Gold Standard Multimedia; 2000.|||Blackman BR, Garcia-Cardena G, Gimbrone MA., Jr A new in vitro model to evaluate differential responses of endothelial cells to simulated arterial shear stress waveforms. J. Biomech. Eng. 2002;124:397–407.|||Wang Y, Yates F, Naveiras O, Ernst P, Daley GQ. Embryonic stemcell-derived hematopoietic stem cells. Proc. Natl Acad. Sci. USA. 2005;102:19081–19086.|||Tiboni GM, Marotta F, Barbacane L. Production of axial skeletalmalformations with the nitric oxide synthesis inhibitorNG-nitro-l-argininemethyl ester (L-NAME) in the mouse. Birth Defects Res. B Dev. Reprod. Toxicol. 2007;80:28–33.