title: Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling.
abstract: Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. In this study, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib), and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in ANGPTL2-stimulated CD34(+) cells showed a strong MYC activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. ANGPTL2 can increase NOTCH activation in cultured cells and ANGPTL receptor interacted with NOTCH to regulate NOTCH cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets.
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Lin
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Emily N
authors.initials: EN
authors.lastname: Price
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Sonja
authors.initials: S
authors.lastname: Boatman
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Hagedorn
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Eirini
authors.initials: E
authors.lastname: Trompouki
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Satishchandran
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Carspecken
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Audrey
authors.initials: A
authors.lastname: Uong
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: DiBiase
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Canver
authors.affiliation: Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Dahlberg
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, United States.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Department of Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: White
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000091304:Angiopoietin-Like Protein 1; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D011485:Protein Binding; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D059008:Time-Lapse Imaging; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C485792:ANGPTL2 protein, human; D000091304:Angiopoietin-Like Protein 1; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C504920:Angptl1 protein, zebrafish; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D051880:Receptors, Notch; D029961:Zebrafish Proteins; C504921:angptl2b protein, zebrafish
keywords: LILRB2; angiopoietin-like proteins; developmental biology; hematopoietic stem and progenitor cells; myc; notch; stem cells; zebrafish