Restoration of Runx1 Expression in the Tie2 Cell Compartment Rescues Definitive Hematopoietic Stem Cells and Extends Life of Runx1 Knockout Animals Until Birth

Authors

  • Anna Liakhovitskaia,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Ruby Gribi,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Evangelos Stamateris,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Gaelle Villain,

    1. Université Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique UMR7622, Laboratoire de Biologie du Développement, Paris, France
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  • Thierry Jaffredo,

    1. Université Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique UMR7622, Laboratoire de Biologie du Développement, Paris, France
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  • Ron Wilkie,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Derek Gilchrist,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Jian Yang,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Janice Ure,

    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Alexander Medvinsky

    Corresponding author
    1. Ontogeny of Haematopoietic Stem Cells Group, Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
    • Ontogeny of Hematopoietic Stem Cells Laboratory, Institute for Stem Cell Research, University of Edinburgh, Edinburgh EH9 3JQ, Scotland, U.K
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    • Telephone: +44 (0)131 650 5888; Fax: +44 (0)131 650 7773


  • Author contributions: A.L.: collection and/or assembly of data, data analysis and interpretation; manuscript writing; final approval of manuscript; R.G.: collection and assembly of data, data analysis and interpretation; E.S., R.W., D.G., and J.Y.: collection of data; G.V.: collection and assembly of data; T.J.: data analysis and interpretation; J.U.: generation of mice, support of transplantation experiments; A.M.: conception and design; financial support; data analysis and interpretation; manuscript writing; final approval of manuscript. A.L. and R.G. contributed equally to this work.

  • First published online in STEM CELLSEXPRESS March 26, 2009.

Abstract

Mice deficient in the runt homology domain transcription factor Runx1/AML1 fail to generate functional clonogenic hematopoietic cells and die in utero by embryonic day 12.5. We previously generated Runx1 reversible knockout mice, in which the Runx1 locus can be restored by Cre-mediated recombination. We show here that selective restoration of the Runx1 locus in the Tie2 cell compartment rescues clonogenic hematopoietic progenitors in early Runx1-null embryos and rescues lymphoid and myeloid lineages during fetal development. Furthermore, fetal liver cells isolated from reactivated Runx1 embryos are capable of long-term multilineage lymphomyeloid reconstitution of adult irradiated recipients, demonstrating the rescue of definitive hematopoietic stem cells. However, this rescue of the definitive hematopoietic hierarchy is not sufficient to rescue the viability of animals beyond birth, pointing to an essential role for Runx1 in other vital developmental processes. STEM CELLS 2009;27:1616–1624

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