title: Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis.
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.
authors: 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.
authors: Miguel F
authors: MF
authors: Diaz
authors: 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.
authors: Nan
authors: N
authors: Li
authors: 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.
authors: Hyun Jung
authors: HJ
authors: Lee
authors: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Luigi
authors: L
authors: Adamo
authors: 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.
authors: Siobahn M
authors: SM
authors: Evans
authors: Department of Bioengineering, Rice University, Houston, TX 77030.
authors: Hannah E
authors: HE
authors: Willey
authors: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
authors: Natasha
authors: N
authors: Arora
authors: Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 Wyss Institute for Biologically Inspired Engineering at Harvard University and Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115 Wyss Institute for Biologically Inspired Engineering at Harvard University and Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Yu-Suke
authors: YS
authors: Torisawa
authors: Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA 02115.
authors: Dwayne A
authors: DA
authors: Vickers
authors: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
authors: Samantha A
authors: SA
authors: Morris
authors: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
authors: Olaia
authors: O
authors: Naveiras
authors: Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA 02115.
authors: Shashi K
authors: SK
authors: Murthy
authors: Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 Wyss Institute for Biologically Inspired Engineering at Harvard University and Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115 Wyss Institute for Biologically Inspired Engineering at Harvard University and Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Donald E
authors: DE
authors: Ingber
authors: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA 02115 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 guillermo_garcia-cardena@hms.harvard.edu george.daley@childrens.harvard.edu pamela.l.wenzel@uth.tmc.edu.
authors: George Q
authors: GQ
authors: Daley
authors: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 guillermo_garcia-cardena@hms.harvard.edu george.daley@childrens.harvard.edu pamela.l.wenzel@uth.tmc.edu.
authors: Guillermo
authors: G
authors: García-Cardeña
authors: 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 guillermo_garcia-cardena@hms.harvard.edu george.daley@childrens.harvard.edu pamela.l.wenzel@uth.tmc.edu.
authors: Pamela L
authors: PL
authors: Wenzel
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D008650:Mesonephros / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone