Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling.
- Howard Hughes Medical Institute, Boston's Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, United States
- Fred Hutchinson Cancer Research Center, United States
- University of Texas Southwestern Medical Center, United States
- Brigham and Women's Hospital, United States
- 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.
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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).
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© 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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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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