Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

Authors

  • Arthur J. Simonnet,

    1. Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat à l'Energie Atomique (CEA), Evry, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U733 (Unité Mixte de Recherche [UMR] INSERM-CEA-Paris XI)Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France
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  • Johnny Nehmé,

    1. Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat à l'Energie Atomique (CEA), Evry, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U733 (Unité Mixte de Recherche [UMR] INSERM-CEA-Paris XI)Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France
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  • Pierre Vaigot,

    1. Institute of Cellular and Molecular Radiation Biology, Department of Genetic Instability, Recombination and Repair, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France and UMR 217 (UMR CEA-Centre National de la Recherche Scientifique)Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France
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  • Vilma Barroca,

    1. Laboratory of Gametogenesis, Apoptosis, Genotoxicity, Institute of Cellular and Molecular Radiation Biology, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France
    2. Institut National de la Santé et de la Recherche Médicale U566 (UMR INSERM-CEA-PARIS VII)Boston, Massachusetts, USA
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  • Philippe Leboulch,

    1. Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat à l'Energie Atomique (CEA), Evry, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U733 (Unité Mixte de Recherche [UMR] INSERM-CEA-Paris XI)Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France
    3. Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • Diana Tronik-Le Roux

    Corresponding author
    1. Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat à l'Energie Atomique (CEA), Evry, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U733 (Unité Mixte de Recherche [UMR] INSERM-CEA-Paris XI)Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France
    • CEA/iMETI/LBF, 2 rue Gaston Crémieux, 91,057 Evry, France
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    • Telephone: 33-1-60-87-34-78; Fax: 33-1-60-87-34-98


  • Author contributions: A.J.S.: Conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; J.N., P.V.: Conception and design, collection and/or assembly of data, data analysis and interpretation; V.B.: Provision of study material or patients; P.L.: Manuscript writing; D.T.-L.: Conception and design, data analysis and interpretation, manuscript writing.

  • First published online in STEM CELLSExpress March 19, 2009

Abstract

Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding “side population (SP)” early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SPSK cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit+Sca-1+Lin−/low (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150+Flk2 and CD150Flk2+ cells, respectively. CD150+ KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not age-matched controls, allowed engraftment and significant hematopoietic contribution from transplanted congenic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice. STEM CELLS 2009;27:1400–1409

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