Self-Renewal of the Long-Term Reconstituting Subset of Hematopoietic Stem Cells Is Regulated by Ikaros§

Authors

  • Peter Papathanasiou,

    Corresponding author
    1. Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    2. Present Address: Australian Phenomics Facility, Australian National University, ACT 0200, Australia
    • Australian Phenomics Facility, Australian National University, ACT 0200, Australia
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    • Telephone: 61-2-6125-1329; Fax: 61-2-6125-1381

  • Joanne L. Attema,

    1. Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
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  • Holger Karsunky,

    1. Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    2. Present Address: Cellerant Therapeutics, San Carlos, California 94070, USA
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  • Naoki Hosen,

    1. Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    2. Present Address: Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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  • Yovina Sontani,

    1. Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia
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  • Gerard F. Hoyne,

    1. Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia
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  • Robert Tunningley,

    1. Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia
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  • Stephen T. Smale,

    1. Howard Hughes Medical Institute, Molecular Biology Institute, and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA
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  • Irving L. Weissman

    1. Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
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  • Author contributions: P.P.: Conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.L.A. and H.K.: Conception and design, collection and assembly of data, data analysis and interpretation, final approval of manuscript; N.H. and G.F.H.: Collection and assembly of data, data analysis and interpretation, final approval of manuscript; Y.S. and R.T.: Collection and assembly of data, final approval of manuscript; S.T.S. and I.L.W.: Financial support, data analysis and interpretation, final approval of manuscript.

  • First published online in STEM CELLS EXPRESS October 8, 2009.

  • §

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

Abstract

Hematopoietic stem cells (HSCs) are rare, ancestral cells that underlie the development, homeostasis, aging, and regeneration of the blood. Here we show that the chromatin-associated protein Ikaros is a crucial self-renewal regulator of the long-term (LT) reconstituting subset of HSCs. Ikaros, and associated family member proteins, are highly expressed in self-renewing populations of stem cells. Ikaros point mutant mice initially develop LT-HSCs with the surface phenotype cKit+Thy1.1(lo)Lin(-/lo)Sca1+Flk2-CD150+ during fetal ontogeny but are unable to maintain this pool, rapidly losing it within two days of embryonic development. A synchronous loss of megakaryocyte/erythrocyte progenitors results, along with a fatal, fetal anemia. At this time, mutation of Ikaros exerts a differentiation defect upon common lymphoid progenitors that cannot be rescued with an ectopic Notch signal in vitro, with hematopoietic cells preferentially committing to the NK lineage. Althoughdispensable for the initial embryonic development of blood, Ikaros is clearly needed for maintenance of this tissue. Achieving successful clinical tissue regeneration necessitates understanding degeneration, and these data provide a striking example by a discrete genetic lesion in the cells underpinning tissue integrity during a pivotal timeframe of organogenesis. STEM CELLS 2009;27:3082–3092

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