Two distinct Flk-1+ mesoderm, hemangiogenic and cardiogenic, establish the functional circulatory system. We recently made progress in further identifying Flk-1+ hemangiogenic and cardiogenic mesoderm by the PDGFR1 expression. Specifically, while Flk-1+PDGFR1- hemangiogenic mesoderm can generate hematopoietic and endothelial cells, Flk-1+PDGFR1+ cardiogenic mesoderm can generate endothelial, smooth muscle cells and cardiomyocytes. However, our understanding of how the Flk-1+ mesoderm is specified is currently limiting. Intriguingly, there seems to be an antagonistic relationship between hematopoietic/vascular and cardiac outcome. Our preliminary studies suggest that we can skew the Flk-1+ mesoderm outcome by temporally modulating expression of the hemangiogenic transcription factors. Specifically, when ER71, GATA2 and Scl were temporally co-expressed during the mesoderm formation and patterning stage, only the Flk-1+PDGFR1- hemangiogenic mesoderm was formed. At the same time, no Flk-1+PDGFR1+ cardiogenic mesoderm was formed. Further characterization of the ER71, GATA2, and Scl mediated combinatorial molecular function would provide insights into the mechanisms by which hemangioblast lineage commitment occurs.
In aim 1, we will test the hypothesis that hemangiogenic mesoderm specification occurs at the expense of cardiogenic mesoderm in pluripotent stem cells and developing embryos. The hematopoietic, endothelial cell and cardiogenic potential of inducible ER71- GATA2-Scl pluripotent stem cells and embryos will be fully determined.
In aim 2, we will test the hypothesis that hemangioblast formation requires ER71, GATA2 and Scl functional interaction, which can be elucidated by characterizing their downstream gene regulatory networks.
In aim 3, we will test the hypothesis that pluripotent stem derived hemangioblasts can generate functional hematopoietic and endothelial cells in vivo. We will determine the full in vivo hematopoietic and endothelial cell potential of induced hemangioblasts. Successful completion of the proposed studies will have impact on both basic and applied science. Ultimately, we will have a deeper understanding of how the hematopoietic system is established during embryogenesis. This topic is most fundamental to the developmental biology of hematopoietic, vascular and cardiovascular fields. We envision that """"""""PURE"""""""" hemangioblasts can be obtained from any pluripotent stem cells by """"""""temporally"""""""" modulating ER71, GATA2 and Scl expression. Thus, positive outcome from the current proposed studies would be directly applicable to regenerative medicine utilizing pluripotent stem cells in the future.

Public Health Relevance

This grant proposal is to understand how blood and blood vessels are established in the developing mouse embryo. This goal will be achieved by characterizing embryonic stem cells and transgenic mice co-expressing developmentally critical master genes that regulate blood and blood vessel development. The outcome of this study is highly relevant to basic research and regenerative medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-F (02))
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Thomas, John
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Washington University
Schools of Medicine
Saint Louis
United States
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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:
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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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