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

eLife

Cheng Cheng Zhang¹  Richard M White²  Irwin D Bernstein³  Stuart H Orkin⁴  Zhigang Lu⁵  Ann Dahlberg⁶  Leonard I Zon⁶  Audrey Uong⁷  Eirini Trompouki⁷  Song Yang⁷  Matthew C Canver⁷  Sruthi Satishchandran⁷  Charles W Carspecken⁷  Michelle I Lin⁷  Elliott J Hagedorn⁷  Anthony DiBiase⁷  Sonja Boatman⁷  Emily N Price⁷  Jon C Aster⁷ 

[1]Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States

[2]Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States

[3]Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States

[4]Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, United States

[5]Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States

[6]Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, United States

[7]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

关键词: angiopoietin-like protein;    notch;    hematopoietic stem;    LILRB2;    myc;    progenitor cells;   

DOI  :  10.7554/eLife.05544

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown