Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling
Michelle I Lin,
Emily N Price,
Sonja Boatman,
Elliott J Hagedorn,
Eirini Trompouki,
Sruthi Satishchandran,
Charles W Carspecken,
Audrey Uong,
Anthony DiBiase,
Song Yang,
Matthew C Canver,
Ann Dahlberg,
Zhigang Lu,
Cheng Cheng Zhang,
Stuart H Orkin,
Irwin D Bernstein,
Jon C Aster,
Richard M White,
Leonard I Zon
Affiliations
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
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
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
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
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
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
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
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
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
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
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
Ann Dahlberg
Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States
Zhigang Lu
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States
Cheng Cheng Zhang
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States
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; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States
Irwin D Bernstein
Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States
Jon C Aster
Department of Pathology, Brigham and Women's Hospital, Boston, United States
Richard M White
Department of Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, United States; Department of Genetics, Memorial Sloan Kettering Cancer Center, New York, United States; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States
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
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.
