Role of SOX17 in hematopoietic development from human embryonic stem cells

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  • Yaeko Nakajima-Takagi
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
  • Mitsujiro Osawa
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
  • Motohiko Oshima
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
  • Haruna Takagi
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
  • Satoru Miyagi
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
  • Mitsuhiro Endoh
    JST, CREST, Tokyo, Japan;
  • Takaho A. Endo
    RIKEN Research Center for Allergy and Immunology, Yokohama, Japan;
  • Naoya Takayama
    Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; and
  • Koji Eto
    Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; and
  • Tetsuro Toyoda
    RIKEN Genomic Sciences Center, Yokohama, Japan;
  • Haruhiko Koseki
    JST, CREST, Tokyo, Japan;
  • Hiromitsu Nakauchi
    Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
  • Atsushi Iwama
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;

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<jats:title>Abstract</jats:title><jats:p>To search for genes that promote hematopoietic development from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), we overexpressed several known hematopoietic regulator genes in hESC/iPSC-derived CD34+CD43− endothelial cells (ECs) enriched in hemogenic endothelium (HE). Among the genes tested, only Sox17, a gene encoding a transcription factor of the SOX family, promoted cell growth and supported expansion of CD34+CD43+CD45−/low cells expressing the HE marker VE-cadherin. SOX17 was expressed at high levels in CD34+CD43− ECs compared with low levels in CD34+CD43+CD45− pre-hematopoietic progenitor cells (pre-HPCs) and CD34+CD43+CD45+ HPCs. Sox17-overexpressing cells formed semiadherent cell aggregates and generated few hematopoietic progenies. However, they retained hemogenic potential and gave rise to hematopoietic progenies on inactivation of Sox17. Global gene-expression analyses revealed that the CD34+CD43+CD45−/low cells expanded on overexpression of Sox17 are HE-like cells developmentally placed between ECs and pre-HPCs. Sox17 overexpression also reprogrammed both pre-HPCs and HPCs into HE-like cells. Genome-wide mapping of Sox17-binding sites revealed that Sox17 activates the transcription of key regulator genes for vasculogenesis, hematopoiesis, and erythrocyte differentiation directly. Depletion of SOX17 in CD34+CD43− ECs severely compromised their hemogenic activity. These findings suggest that SOX17 plays a key role in priming hemogenic potential in ECs, thereby regulating hematopoietic development from hESCs/iPSCs.</jats:p>

Journal

  • Blood

    Blood 121 (3), 447-458, 2013-01-17

    American Society of Hematology

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