Sox17-Mediated Maintenance of Fetal Intra-Aortic Hematopoietic Cell Clusters

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  • Ikuo Nobuhisa
    Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
  • Mitsujiro Osawa
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
  • Mami Uemura
    Department of Experimental Animal Model for Human Disease, Center for Experimental Animal, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
  • Yoko Kishikawa
    Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo, Kumamoto, Japan
  • Maha Anani
    Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
  • Kaho Harada
    Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
  • Haruna Takagi
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
  • Kiyoka Saito
    Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
  • Masami Kanai-Azuma
    Department of Experimental Animal Model for Human Disease, Center for Experimental Animal, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
  • Yoshiakira Kanai
    Department of Veterinary Anatomy, Graduate School of Agricultural and Life Science, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
  • Atsushi Iwama
    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
  • Tetsuya Taga
    Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan

Description

During mouse development, definitive hematopoiesis is first detected around embryonic day 10.5 (E10.5) in the aorta-gonad-mesonephros (AGM) region, which exhibits intra-aortic cell clusters. These clusters are known to contain hematopoietic stem cells (HSCs). On the other hand, it is not clear how the cells in such clusters maintain their HSC phenotype and how they are triggered to differentiate. Here we found that an endodermal transcription factor marker, Sox17, and other F-group (SoxF) proteins, Sox7 and Sox18, were expressed in E10.5 intra-aortic cell clusters. Forced expression of any of these SoxF proteins, particularly Sox17, in E10.5 AGM CD45(low) c-Kit(high) cells, which are the major component of intra-aortic clusters, led to consistent formation of cell clusters in vitro during several passages of cocultures with stromal cells. Cluster-forming cells with constitutive Sox17 expression retained long-term bone marrow reconstitution activity in vivo. Notably, shutdown of exogenously introduced Sox17 gene expression resulted in immediate hematopoietic differentiation. These results indicate that SoxF proteins, especially Sox17, contribute to the maintenance of cell clusters containing HSCs in the midgestation AGM region. Furthermore, SoxF proteins play a pivotal role in controlling the HSC fate decision between indefinite self-renewal and differentiation during fetal hematopoiesis.

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