title: Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.
abstract: Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, specifically PI(3)Kγ. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.
authors.affiliation: 1] Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA [2] Chemical Biology Program, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Pulin
authors.initials: P
authors.lastname: Li
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Lahvic
authors.affiliation: 1] Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA [2] Department of Hematology and Oncology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Binder
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Pugach
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Riley
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Tamplin
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Teresa V
authors.initials: TV
authors.lastname: Bowman
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Francesca G
authors.initials: FG
authors.lastname: Barrett
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Heffner
authors.affiliation: Department of Haematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: McKinney-Freeman
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Schlaeger
authors.affiliation: Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: 1] Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA [2] Chemical Biology Program, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015027:Zebrafish / Q000196:embryology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D018808:Transcription Factor AP-1; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D019869:Phosphatidylinositol 3-Kinases; D015126:8,11,14-Eicosatrienoic Acid