The Runx1-CBFbeta transcription factor is required for the emergence of all definitive hematopoietic cells. It is the earliest specific marker of sites from which hematopoietic stem and progenitor cells are produced in the conceptus. Runx1 is expressed in endothelial cells, mesenchymal cells, and in intra-aortic hematopoietic clusters, and in all committed hematopoietic progenitors and transplantable stem cells. We hypothesize that Runx1-CBFbeta is required, at least in part, for the transition between """"""""hemogenic endothelium"""""""" and hematopoietic cells during fetal development. However, if Runx1 is deleted in adult mice, after hematopoiesis is established, long-term repopulating hematopoietic stem cells persist, committed erythroid, myeloid, and megakaryocytic progenitors increase in number, and both erythropoiesis and terminal granulocyte differentiation are normal. Thus, there is an absolute requirement for Runx1-CBFbeta to establish hematopoiesis in the fetus, but not to maintain all aspects of it in the adult. One of our goals is to define the developmental window and cell types in which Runx1-CBFbeta is required to specify definitive hematopoiesis in the conceptus.
A second aim follows up on recent findings that the placenta may be a source of hematopoietic stem cells. We will determine where in the placenta hematopoietic stem cells reside, and whether they differentiate from endothelial cells in the allantois or in the placental labyrinth. Finally, we will attempt to identify the signaling sources that induce the first wave of Runx1 expression and definitive hematopoiesis in the conceptus. We will specifically examine whether Hedgehog, the upstream component of a signaling cascade required for definitive hematopoiesis in zebrafish, activates Runx1 expression and definitive hematopoiesis in the mouse conceptus. Together these aims will contribute to our understanding of the earliest events that establish definitive hematopoiesis in the mouse conceptus, and should help guide efforts to produce blood cells from embryonic sources in vitro.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-HEME-B (02))
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Thomas, John
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Yzaguirre, Amanda D; Howell, Elizabeth D; Li, Yan et al. (2018) Runx1 is sufficient for blood cell formation from non-hemogenic endothelial cells in vivo only during early embryogenesis. Development 145:
Tober, Joanna; Maijenburg, Marijke M W; Li, Yan et al. (2018) Maturation of hematopoietic stem cells from prehematopoietic stem cells is accompanied by up-regulation of PD-L1. J Exp Med 215:645-659
Yzaguirre, Amanda D; de Bruijn, Marella F T R; Speck, Nancy A (2017) The Role of Runx1 in Embryonic Blood Cell Formation. Adv Exp Med Biol 962:47-64
Zhen, Tao; Kwon, Erika M; Zhao, Ling et al. (2017) Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11. Blood 130:2431-2442
Li, Yan; Gao, Long; Hadland, Brandon et al. (2017) CD27 marks murine embryonic hematopoietic stem cells and type II prehematopoietic stem cells. Blood 130:372-376
Lis, Raphael; Karrasch, Charles C; Poulos, Michael G et al. (2017) Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature 545:439-445
Speck, Nancy A (2016) Stress Can Be a Good Thing for Blood Formation. Cell Stem Cell 19:279-80
Yzaguirre, Amanda D; Speck, Nancy A (2016) Insights into blood cell formation from hemogenic endothelium in lesser-known anatomic sites. Dev Dyn 245:1011-28
Yzaguirre, Amanda D; Speck, Nancy A (2016) Extravascular endothelial and hematopoietic islands form through multiple pathways in midgestation mouse embryos. Dev Biol 415:111-121
Yzaguirre, Amanda D; Padmanabhan, Arun; de Groh, Eric D et al. (2015) Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos. Elife 4:e07780

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