Stage-Specific Roles for Cxcr4 Signaling in Murine Hematopoietic Stem/Progenitor Cells in the Process of Bone Marrow Repopulation

Authors

  • Chen-Yi Lai,

    1. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    2. Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Satoshi Yamazaki,

    1. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Motohito Okabe,

    1. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Sachie Suzuki,

    1. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Yoshihiro Maeyama,

    1. Upper GI Surgery Division, Department of Surgery, Hyogo College of Medicine, Kobe, Japan
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  • Yasuaki Iimura,

    1. Kushiro City General Hospital, Kushiro, Japan
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  • Masafumi Onodera,

    1. Department of Genetics, National Research Institute of Child Health and Development, Tokyo, Japan
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  • Shigeru Kakuta,

    1. Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    2. Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan
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  • Yoichiro Iwakura,

    1. Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    2. Division of Experimental Animal Immunology, Research Institute for Biomedical Sciences/Graduate School of Biological Science, Tokyo University of Science, Tokyo, Japan
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  • Masanori Nojima,

    1. Division of Advanced Medicine Promotion, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Makoto Otsu,

    Corresponding author
    1. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    2. Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • Correspondence: Makoto Otsu, Ph.D., M.D., Stem Cell Bank and Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Telephone: +81-3-6409-2342; Fax: +81-3-6409-2343; e-mail: motsu@ims.u-tokyo.ac.jp; or Hiromitsu Nakauchi, Ph.D., M.D., Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Telephone: +81-3-5449-5330; Fax: +81-3-5449-5451; e-mail: nakauchi@ims.u-tokyo.ac.jp

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  • Hiromitsu Nakauchi

    Corresponding author
    1. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • Correspondence: Makoto Otsu, Ph.D., M.D., Stem Cell Bank and Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Telephone: +81-3-6409-2342; Fax: +81-3-6409-2343; e-mail: motsu@ims.u-tokyo.ac.jp; or Hiromitsu Nakauchi, Ph.D., M.D., Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Telephone: +81-3-5449-5330; Fax: +81-3-5449-5451; e-mail: nakauchi@ims.u-tokyo.ac.jp

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Abstract

Hematopoietic cell transplantation has proven beneficial for various intractable diseases, but it remains unclear how hematopoietic stem/progenitor cells (HSPCs) home to the bone marrow (BM) microenvironment, initiate hematopoietic reconstitution, and maintain life-long hematopoiesis. The use of newly elucidated molecular determinants for overall HSPC engraftment should benefit patients. Here, we report that modification of C-X-C chemokine receptor type 4 (Cxcr4) signaling in murine HSPCs does not significantly affect initial homing/lodging events, but leads to alteration in subsequent BM repopulation kinetics, with observations confirmed by both gain- and loss-of-function approaches. By using C-terminal truncated Cxcr4 as a gain-of-function effector, we demonstrated that signal augmentation likely led to favorable in vivo repopulation of primitive cell populations in BM. These improved features were correlated with enhanced seeding efficiencies in stromal cell cocultures and altered ligand-mediated phosphorylation kinetics of extracellular signal-regulated kinases observed in Cxcr4 signal-augmented HSPCs in vitro. Unexpectedly, however, sustained signal enhancement even with wild-type Cxcr4 overexpression resulted in impaired peripheral blood (PB) reconstitution, most likely by preventing release of donor hematopoietic cells from the marrow environment. We thus conclude that timely regulation of Cxcr4/CXCR4 signaling is key in providing donor HSPCs with enhanced repopulation potential following transplantation, whilst preserving the ability to release HSPC progeny into PB for improved transplantation outcomes. Stem Cells 2014;32:1929–1942

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