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dc.contributor.advisorNorth, Trista Elizabeth
dc.contributor.authorCarroll, Kelli Jane
dc.date.accessioned2014-06-06T14:11:20Z
dc.date.issued2014-06-06
dc.date.submitted2014
dc.identifier.citationCarroll, Kelli Jane. 2014. The Role of Estrogen Signaling in the Induction, Specification, and Proliferation of Hematopoietic Stem Cells. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:11446en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12269823
dc.description.abstractHematopoietic Stem Cells (HSCs) are characterized by their ability to both self-renew and give rise to all lineages of the blood system. A recent chemical genetic screen identified 17β-estradiol (estrogen) as a novel modifier of the expression of the conserved HSC markers runx1 and cmyb in the Aorta-Gonad-Mesonephros of developing zebrafish. Exposure to exogenous estrogen during the development of the hematopoietic niche impeded specification of hemogenic endothelium and the subsequent emergence of HSCs via antagonism of somitic-derived VEGF signaling. Conversely, inhibition of endogenous estrogen activity increased the number of functional HSCs present in the embryo and resulted in higher expression of VEGF target genes, suggesting that endogenous estrogen acts to define the ventral limit of VEGF activity and hemogenic endothelial specification. In contrast, when embryos were exposed to estrogen after niche specification, markers of HSCs were increased, indicating that estrogen has a biphasic effect on HSC formation; this effect appears to be at least partially mediated by enhanced cell cycling of the HSC population. Estrogen exposure during primitive erythropoiesis likewise increased the number of erythroid progenitors in the embryo, but their maturation into functional erythrocytes was impaired. Inhibition of erythrocyte maturation is also conserved in a mammalian model of in utero excess estrogen, causing propensity for embryonic lethality. Treatment of adult zebrafish with exogenous estrogen after ablation of the hematopoietic system by irradiation revealed that elevated estrogen levels improved hematopoietic regeneration. Consistent with a role for hormonal regulation of HSC homeostasis, accelerated recovery of hematopoietic stem and progenitor numbers was observed in female fish compared to males, suggesting an endogenous difference in regenerative capacity between the sexes. Together, these data identify multiple distinct roles for estrogen in HSC biology and indicate it is a physiologically relevant regulator of HSC development and homeostasis.en_US
dc.language.isoen_USen_US
dash.licenseLAA
dc.subjectDevelopmental biologyen_US
dc.subjectBlooden_US
dc.subjectDevelopmenten_US
dc.subjectEstrogenen_US
dc.subjectRegenerationen_US
dc.subjectZebrafishen_US
dc.titleThe Role of Estrogen Signaling in the Induction, Specification, and Proliferation of Hematopoietic Stem Cellsen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorCarroll, Kelli Jane
dc.date.available2014-06-06T14:11:20Z
thesis.degree.date2014en_US
thesis.degree.disciplineBiology: Medical Sciences, Division ofen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberBurns, Carolineen_US
dc.contributor.committeeMemberD'Amore, Patriciaen_US
dc.contributor.committeeMemberHock, Hannoen_US
dc.contributor.committeeMemberArmstrong, Scotten_US
dc.contributor.committeeMemberGalloway, Jennaen_US
dc.contributor.committeeMemberCantor, Alanen_US
dc.contributor.committeeMemberJin, Suk-Wonen_US
dash.contributor.affiliatedCarroll, Kelli Jane


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