Tissue-Specific Stem Cells

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

  1. Peter Papathanasiou1,4,¶,*,
  2. Joanne L. Attema1,
  3. Holger Karsunky1,5,
  4. Naoki Hosen1,6,
  5. Yovina Sontani3,
  6. Gerard F. Hoyne3,
  7. Robert Tunningley3,
  8. Stephen T. Smale2,
  9. Irving L. Weissman1

Article first published online: 8 OCT 2009

DOI: 10.1002/stem.232

Issue

STEM CELLS

STEM CELLS

Volume 27, Issue 12, pages 3082–3092, December 2009

Additional Information

How to Cite

Papathanasiou, P., Attema, J. L., Karsunky, H., Hosen, N., Sontani, Y., Hoyne, G. F., Tunningley, R., Smale, S. T. and Weissman, I. L. (2009), Self-Renewal of the Long-Term Reconstituting Subset of Hematopoietic Stem Cells Is Regulated by Ikaros. STEM CELLS, 27: 3082–3092. doi: 10.1002/stem.232

Author Information

  1. 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. 2

    Howard Hughes Medical Institute, Molecular Biology Institute, and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA

  3. 3

    Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia

  4. 4

    Present Address: Australian Phenomics Facility, Australian National University, ACT 0200, Australia

  5. 5

    Present Address: Cellerant Therapeutics, San Carlos, California 94070, USA

  6. 6

    Present Address: Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

  1. Telephone: 61-2-6125-1329; Fax: 61-2-6125-1381

*Australian Phenomics Facility, Australian National University, ACT 0200, Australia

  1. †

    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.

  2. ‡

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

  3. §

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

  4. Telephone: 61-2-6125-1329; Fax: 61-2-6125-1381

Publication History

  1. Issue published online: 14 DEC 2009
  2. Article first published online: 8 OCT 2009
  3. Accepted manuscript online: 8 OCT 2009 12:00AM EST
  4. Manuscript Accepted: 21 SEP 2009
  5. Manuscript Received: 30 JUL 2009

Funded by

  • NIH. Grant Numbers: 5P01 DK53074, R01 CA086065, R01 DK43726
  • National Health & Medical Research Council CJ Martin Fellowship
  • and Japanese Society of Promotion of Science Fellowship

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Keywords:

  • Hematopoietic stem cells;
  • Ikaros;
  • Fetal liver

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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