HEMANGIOBLAST DEVELOPMENT AND REGULATION

Summary

Principal Investigator: Kyunghee Choi
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 1996-08-01 - 2015-11-30
more information: NIH RePORT

Top Publications

  1. pmc ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification
    Dongjun Lee
    National Research Laboratory, Department of Biological Science, KAIST, Daejeon, Korea
    Cell Stem Cell 2:497-507. 2008
  2. pmc Differentiation of mouse embryonic stem cells into blood
    Yunglin D Ma
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
    Curr Protoc Stem Cell Biol . 2008
  3. pmc Molecular basis for Flk1 expression in hemato-cardiovascular progenitors in the mouse
    Hiroyuki Ishitobi
    Department of Anatomy and Embryology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1 1 1 Tennodai, Tsukuba, Ibaraki, Japan
    Development 138:5357-68. 2011
  4. pmc Paxillin contracts the osteoclast cytoskeleton
    Wei Zou
    Department of Pathology and Immunology, School of Medicine, Washington University, St Louis, MO 63110, USA
    J Bone Miner Res 27:2490-500. 2012
  5. pmc A Bioreducible Polymer for Efficient Delivery of Fas-Silencing siRNA into Stem Cell Spheroids and Enhanced Therapeutic Angiogenesis
    Min Suk Shim
    Department of Biomedical Engineering, Washington University, St Louis, MO 63130 USA Current address The Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Chemistry and Biochemistry and School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332 USA
    Angew Chem Int Ed Engl 51:11899-903. 2012
  6. ncbi Enhanced hemangioblast generation and improved vascular repair and regeneration from embryonic stem cells by defined transcription factors
    Fang Liu
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    Stem Cell Reports 1:166-82. 2013

Research Grants

  1. Chemical Induction of Cardiomyogenesis
    Charles C Hong; Fiscal Year: 2013

Detail Information

Publications6

  1. pmc ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification
    Dongjun Lee
    National Research Laboratory, Department of Biological Science, KAIST, Daejeon, Korea
    Cell Stem Cell 2:497-507. 2008
    ..Collectively, we provide compelling evidence that ER71 functions downstream of BMP, Notch, and Wnt signals and regulates FLK1(+) mesoderm, blood, and vessel development...
  2. pmc Differentiation of mouse embryonic stem cells into blood
    Yunglin D Ma
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
    Curr Protoc Stem Cell Biol . 2008
    ..The protocols provided in this unit describe methods of maintaining and differentiating mouse ES cells as well as identifying and isolating hematopoietic progenitors by utilizing flow cytometry and progenitor assays...
  3. pmc Molecular basis for Flk1 expression in hemato-cardiovascular progenitors in the mouse
    Hiroyuki Ishitobi
    Department of Anatomy and Embryology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1 1 1 Tennodai, Tsukuba, Ibaraki, Japan
    Development 138:5357-68. 2011
    ..The enhancer is required for early Flk1 expression and for hemangioblast development during ES differentiation...
  4. pmc Paxillin contracts the osteoclast cytoskeleton
    Wei Zou
    Department of Pathology and Immunology, School of Medicine, Washington University, St Louis, MO 63110, USA
    J Bone Miner Res 27:2490-500. 2012
    ..Thus, in response to RANKL, paxillin associates with myosin IIA to contract the osteoclast cytoskeleton, thereby promoting its bone-degrading capacity...
  5. pmc A Bioreducible Polymer for Efficient Delivery of Fas-Silencing siRNA into Stem Cell Spheroids and Enhanced Therapeutic Angiogenesis
    Min Suk Shim
    Department of Biomedical Engineering, Washington University, St Louis, MO 63130 USA Current address The Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Chemistry and Biochemistry and School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332 USA
    Angew Chem Int Ed Engl 51:11899-903. 2012
    ..The enhanced anti-apoptotic activity of the Fas-silenced hMSCs means that they can be readily formulated as enlarged spheroids to significantly enhance angiogenic efficacy as compared to their smaller counterparts...
  6. ncbi Enhanced hemangioblast generation and improved vascular repair and regeneration from embryonic stem cells by defined transcription factors
    Fang Liu
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    Stem Cell Reports 1:166-82. 2013
    ..ESC-derived, EGS-induced FLK-1(+) hemangioblasts could provide an attractive cell source for future hematopoietic and vascular repair and regeneration. ..

Research Grants30

  1. Chemical Induction of Cardiomyogenesis
    Charles C Hong; Fiscal Year: 2013
    ....