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
Program in Children's Regenerative Medicine, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, and Immunology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030 Program in Children's Regenerative Medicine, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, and Immunology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030 Program in Children's Regenerative Medicine, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, and Immunology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030.
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
J Exp Med. 2015 May 4;212(5):665-80. doi: 10.1084/jem.20142235. Epub 2015 Apr 13.
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.
血流促进发育中胚胎里确定的造血干细胞（HSCs）的出现，然而，由血流动力学力产生的影响造血潜能的信号仍不清楚。在这里，我们表明，流体剪切应力赋予胚胎第9.5天的早期造血组织长期多谱系移植潜能，这是一个以前未被描述为含有造血干细胞的胚胎阶段。对造血的影响部分由壁面剪切应力下游的级联反应介导，该级联反应涉及钙外流和前列腺素E2（PGE2）-环磷酸腺苷（cAMP）-蛋白激酶A（PKA）信号轴的刺激。阻断主动脉-性腺-中肾（AGM）中的PGE2-cAMP-PKA途径可消除造血活性的增强。此外，Ncx1心跳突变体以及AGM的静态培养物，前列腺素合酶的表达水平较低，且cAMP反应元件结合蛋白（CREB）的磷酸化减少。与血流暴露培养物类似，用合成类似物16,16-二甲基-PGE2短暂处理AGM可刺激成年受体更强大的移植和更强的淋巴样重建。这些数据提供了一种机制，通过该机制血流诱导的生物力学力调节造血潜能。
