During mouse embryogenesis, blood cells develop closely together with endothelial cells. Therefore, it has been postulated that hematopoietic and endothelial cells share a common progenitor, the hemangioblast. In the past, we have established that Blast colony forming cells (BL-CFCs) from in vitro differentiated embryonic stem (ES) cells represent the hemangioblast. Recently, BL-CFCs have also been identified from developing embryos. By tracking Flk-1, a receptor tyrosine kinase, and Scl, a basic helix-loop-helix transcription factor, we have demonstrated that Flk-1+SCL- mesoderm first arises in developing embryoid bodies (EBs, in vitro differentiated progeny of embryonic stem cells). Flk-1 + mesoderm then generate Flk- 1+SCL+ cells by upregulating Scl. The initially arising Flk-1+SCL+ cells are enriched for hemangioblasts. Within Flk-1+SCL+ cells, Flk-1 is down regulated to finally generate Flk-1-SCL+ hematopoietic progenitors. We previously identified bone morphogenetic protein (BMP)-4 as a critical inducing factor of Flk-1 + mesoderm. In elucidating molecular mechanisms regulating hemangioblast development, we have identified GATA-2 to be up regulated in the Flk-1+Scl+ cells compared to their progeny blast colony cells. Our preliminary studies indicate that GATA-2 was immediately induced by BMP-4. Importantly, exogenous GATA-2 expression could induce Flk-1 + as well as Scl+ cells. This coincided with an increase in blast and hematopoietic colony formation. Based on these findings, we hypothesize that GATA-2 is a critical regulator linking BMP-4 signaling to hemangioblast and hematopoietic development. We posit that GATA-2 carries out this task by upregulating Flk-1 and Scl expression. To test this hypothesis, we will perform promoter assays, chromatin immunoprecipitation studies, and the ES/EB differentiation model. Ultimately, we hope to establish the BMP-4-GATA-2-Flk-1 axis and the BMP-4-GATA-2-Scl axis in regulating hemangioblast and hematopoietic development. Additionally, In vivo developmental potential of ES-derived Flk-1+Scl+ cells will be investigated. The outcome of this study should be relevant for developmental biology as well as for clinical applications concerning hematologic disorders. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hematopoiesis Study Section (HP)
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Thomas, John
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Washington University
Schools of Medicine
Saint Louis
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Oladipupo, Sunday S; Kabir, Ashraf Ul; Smith, Craig et al. (2018) Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1). Sci Rep 8:14724
Kabir, Ashraf Ul; Lee, Tae-Jin; Pan, Hua et al. (2018) Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis. JCI Insight 3:
Davis, Jennifer A; Koenig, Andrew L; Lubert, Allison et al. (2018) ETS transcription factor Etsrp / Etv2 is required for lymphangiogenesis and directly regulates vegfr3 / flt4 expression. Dev Biol 440:40-52
Lee, Tae-Jin; Shim, Min Suk; Yu, Taekyung et al. (2018) Bioreducible Polymer Micelles Based on Acid-Degradable Poly(ethylene glycol)-poly(amino ketal) Enhance the Stromal Cell-Derived Factor-1? Gene Transfection Efficacy and Therapeutic Angiogenesis of Human Adipose-Derived Stem Cells. Int J Mol Sci 19:
Zhao, Haiyong; Choi, Kyunghee (2017) A CRISPR screen identifies genes controlling Etv2 threshold expression in murine hemangiogenic fate commitment. Nat Commun 8:541
Xu, Can-Xin; Lee, Tae-Jin; Sakurai, Nagisa et al. (2017) ETV2/ER71 regulates hematopoietic regeneration by promoting hematopoietic stem cell proliferation. J Exp Med 214:1643-1653
Park, Changwon; Lee, Tae-Jin; Bhang, Suk Ho et al. (2016) Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol 36:86-96
Lohmann, Felix; Dangeti, Mohan; Soni, Shefali et al. (2015) The DEK Oncoprotein Is a Critical Component of the EKLF/KLF1 Enhancer in Erythroid Cells. Mol Cell Biol 35:3726-38
Liu, Fang; Li, Daofeng; Yu, Yik Yeung Lawrence et al. (2015) Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2. EMBO Rep 16:654-69
Oladipupo, Sunday S; Smith, Craig; Santeford, Andrea et al. (2014) Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111:13379-84

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