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Dev Cell. 2014 May 27;29(4):437-53. doi: 10.1016/j.devcel.2014.04.012.

Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche.

Author information

1
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
2
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
University of Alabama at Birmingham, Birmingham, AL 35294, USA.
4
Carnegie Institution for Science, Baltimore, MD 21218, USA.
5
University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: wgoessling@partners.org.
7
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: tnorth@bidmc.harvard.edu.

Abstract

Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, we report that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizing VEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure to exogenous E2 during vascular niche development significantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.

PMID:
24871948
PMCID:
PMC4469361
DOI:
10.1016/j.devcel.2014.04.012
[Indexed for MEDLINE]
Free PMC Article

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