Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling.

  1. Michelle I Lin
  2. Emily N Price
  3. Sonja Boatman
  4. Elliott J Hagedorn
  5. Eirini Trompouki
  6. Sruthi Satishchandran
  7. Charles W Carspecken
  8. Audrey Uong
  9. Anthony DiBiase
  10. Song Yang
  11. Matthew C Canver
  12. Ann Dahlberg
  13. Zhigang Lu
  14. Cheng Cheng Zhang
  15. Stuart H Orkin
  16. Irwin D Bernstein
  17. Jon C Aster
  18. Richard M White
  19. Leonard I Zon  Is a corresponding author
  1. Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, United States
  2. Fred Hutchinson Cancer Research Center, United States
  3. University of Texas Southwestern Medical Center, United States
  4. Brigham and Women's Hospital, United States
  5. Memorial Sloan Kettering Cancer Center, United States

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. Here, 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.

Article and author information

Author details

  1. Michelle I Lin

    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
    Competing interests
    No competing interests declared.
  2. Emily N Price

    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
    Competing interests
    No competing interests declared.
  3. Sonja Boatman

    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
    Competing interests
    No competing interests declared.
  4. Elliott J Hagedorn

    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
    Competing interests
    No competing interests declared.
  5. Eirini Trompouki

    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
    Competing interests
    No competing interests declared.
  6. Sruthi Satishchandran

    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
    Competing interests
    No competing interests declared.
  7. Charles W Carspecken

    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
    Competing interests
    No competing interests declared.
  8. Audrey Uong

    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
    Competing interests
    No competing interests declared.
  9. Anthony DiBiase

    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
    Competing interests
    No competing interests declared.
  10. Song Yang

    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
    Competing interests
    No competing interests declared.
  11. Matthew C Canver

    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
    Competing interests
    No competing interests declared.
  12. Ann Dahlberg

    Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  13. Zhigang Lu

    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  14. Cheng Cheng Zhang

    Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  15. Stuart H Orkin

    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
    Competing interests
    No competing interests declared.
  16. Irwin D Bernstein

    Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  17. Jon C Aster

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  18. Richard M White

    Department of Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  19. Leonard I Zon

    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
    For correspondence
    zon@enders.tch.harvard.edu
    Competing interests
    Leonard I Zon, I am a founder and stockholder of Fate, Inc. and Scholar Rock, and a scientific advisor for Stemgent.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All zebrafish were housed at the Karp Aquatic Resource Program Facility at Boston Children's Hospital. All protocols were approved by the Animal Care and Use Committee at Boston Children's Hospital and by the Institutional Animal Care and Use Committee (protocol 11-10-2069R).

Copyright

© 2015, Lin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Michelle I Lin
  2. Emily N Price
  3. Sonja Boatman
  4. Elliott J Hagedorn
  5. Eirini Trompouki
  6. Sruthi Satishchandran
  7. Charles W Carspecken
  8. Audrey Uong
  9. Anthony DiBiase
  10. Song Yang
  11. Matthew C Canver
  12. Ann Dahlberg
  13. Zhigang Lu
  14. Cheng Cheng Zhang
  15. Stuart H Orkin
  16. Irwin D Bernstein
  17. Jon C Aster
  18. Richard M White
  19. Leonard I Zon
(2015)
Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling.
eLife 4:e05544.
https://doi.org/10.7554/eLife.05544

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https://doi.org/10.7554/eLife.05544