Individual Hematopoietic Stem Cells in Human Bone Marrow of Patients with Aplastic Anemia or Myelodysplastic Syndrome Stably Give Rise to Limited Cell Lineages

Authors

  • Takamasa Katagiri,

    1. Clinical Laboratory Science, Division of Health Sciences, and Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
    2. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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  • Hiroshi Kawamoto,

    1. Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan
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  • Takashi Nakakuki,

    1. Department of Mechanical Systems Engineering Faculty of Engineering, Kogakuin University, Shinjuku-ku, Tokyo, Japan
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  • Ken Ishiyama,

    1. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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  • Mariko Okada-Hatakeyama,

    1. Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan
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  • Shigeki Ohtake,

    1. Clinical Laboratory Science, Division of Health Sciences, and Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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  • Yu Seiki,

    1. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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  • Kohei Hosokawa,

    1. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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  • Shinji Nakao

    Corresponding author
    1. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
    • Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan
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    • Telephone: +81-76-265-2274; Fax: +81-76-234-4252


  • Author contributions: H.K.: developed the concept of the study and supervised the project, designed the experiments, wrote the paper, and approved the final version of this paper; S.N.: developed the concept of the study and supervised the project, wrote the paper, and approved the final version of this paper; T.K. and T.N.: designed the experiments, performed the experiments and analyzed the data, wrote the paper, and approved the final version of this paper; K.I. and M.O.-H.: designed the experiments and approved the final version of this paper; S.O., Y.S. and K.H. :performed the experiments and analyzed the data, approved the final version of this paper. T.K., H.K., and T.N. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • First published online in STEM CELLSEXPRESS January 12, 2013.

Abstract

Mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene in hematopoietic stem cells (HSCs) results in the loss of glycosylphosphatidylinositol-anchored proteins (GPI-APs) on HSCs, but minimally affects their development, and thus can be used as a clonal maker of HSCs. We analyzed GPI-APs expression on six major lineage cells in a total of 574 patients with bone marrow (BM) failure in which microenvironment itself is thought to be unaffected, including aplastic anemia (AA) or myelodysplastic syndrome (MDS). GPI-APs-deficient (GPI-APs) cells were detected in 250 patients. Whereas the GPI-APs cells were seen in all six lineages in a majority of patients who had higher proportion ([dbmtequ]3%) of GPI-APs cells, they were detected in only limited lineages in 92.9% of cases in the lower proportion (<3%) group. In all 250 cases, the same lineages of GPI-APs cells were detected even after 6–18-month intervals, indicating that the GPI-APs cells reflect hematopoiesis maintained by a self-renewing HSC in most of cases. The frequency of clones with limited lineages seen in mild cases of AA was similar to that in severe cases, and clones with limited lineages were seen even in two health volunteer cases. These results strongly suggest most individual HSCs produce only restricted lineages even in a steady state. While this restriction could reflect heterogeneity in the developmental potential of HSCs, we propose an alternative model in which the BM microenvironment is mosaic in supporting commitment of progenitors toward distinct lineages. Our computer simulation based on this model successfully recapitulated the observed clinical data. STEM CELLS2013;31:536–546

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