Self-renewal of the long-term reconstituting subset of hematopoietic stem cells is regulated by Ikaros

Peter Papathanasiou*, Joanne L. Attema, Holger Karsunky, Naoki Hosen, Yovina Sontani, Gerard F. Hoyne, Robert Tunningley, Stephen T. Smale, Irving L. Weissman

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    33 Citations (Scopus)

    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. Although-dispensable 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.

    Original languageEnglish
    Pages (from-to)3082-3092
    Number of pages11
    JournalStem Cells
    Volume27
    Issue number12
    DOIs
    Publication statusPublished - Dec 2009

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