A Cross-Talk Between Stromal Cell-Derived Factor-1 and Transforming Growth Factor-β Controls the Quiescence/Cycling Switch of CD34+ Progenitors Through FoxO3 and Mammalian Target of Rapamycin

Authors

  • Aurélie Chabanon,

    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Christophe Desterke,

    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Emilie Rodenburger,

    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Denis Clay,

    1. University of Paris-Sud, Institut André Lwoff, Villejuif, France
    2. IFR89, University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Bernadette Guerton,

    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Laetitia Boutin,

    1. Centre de Transfusion Sanguine des Armées, Hôpital Percy, Clamart, France
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  • Annelise Bennaceur-Griscelli,

    1. University of Paris-Sud, Institut André Lwoff, Villejuif, France
    2. Institut National de la Santé et de la Recherche Médicale, U790, Villejuif, France
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  • Olivier Pierre-Louis,

    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Georges Uzan,

    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
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  • Lucile Abecassis,

    1. University of Paris-Sud, Institut André Lwoff, Villejuif, France
    2. Institut National de la Santé et de la Recherche Médicale, U542, Villejuif, France
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  • Marie-Françoise Bourgeade,

    1. University of Paris-Sud, Institut André Lwoff, Villejuif, France
    2. Institut National de la Santé et de la Recherche Médicale, U542, Villejuif, France
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  • Jean-Jacques Lataillade,

    Corresponding author
    1. Centre de Transfusion Sanguine des Armées, Hôpital Percy, Clamart, France
    • Jean-Jacques Lataillade, Jean-Jacques Lataillade, M.D., Ph.D., Centre de Transfusion Sanguine des Armées, BP 410, Clamart, F-92140, France. Telephone: 33-1-41-46-72-60; Fax: 33-1-46-38-82-87

      Marie-Caroline Le Bousse-Kerdilès, Correspondence: Marie-Caroline Le Bousse-Kerdilès, Ph.D., Inserm, U602, 14 Av. Paul-Vaillant Couturier, Villejuif, F-94807, France. Telephone: 33-1-45-59-53-03; Fax: 33-1-47-26-03-19

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  • Marie-Caroline Le Bousse-Kerdilès

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale, U602, Villejuif, France
    2. University of Paris-Sud, Institut André Lwoff, Villejuif, France
    • Jean-Jacques Lataillade, Jean-Jacques Lataillade, M.D., Ph.D., Centre de Transfusion Sanguine des Armées, BP 410, Clamart, F-92140, France. Telephone: 33-1-41-46-72-60; Fax: 33-1-46-38-82-87

      Marie-Caroline Le Bousse-Kerdilès, Correspondence: Marie-Caroline Le Bousse-Kerdilès, Ph.D., Inserm, U602, 14 Av. Paul-Vaillant Couturier, Villejuif, F-94807, France. Telephone: 33-1-45-59-53-03; Fax: 33-1-47-26-03-19

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Abstract

Cell cycle regulation plays a fundamental role in stem cell biology. A balance between quiescence and proliferation of hematopoietic stem cells in interaction with the microenvironment is critical for sustaining long-term hematopoiesis and for protection against stress. We analyzed the molecular mechanisms by which stromal cell-derived factor-1 (SDF-1) exhibited a cell cycle-promoting effect and interacted with transforming growth factor-β (TGF-β), which has negative effects on cell cycle orchestration of human hematopoietic CD34+ progenitor cells. We demonstrated that a low concentration of SDF-1 modulated the expression of key cell cycle regulators such as cyclins, cyclin-dependent kinase inhibitors, and TGF-β target genes, confirming its cell cycle-promoting effect. We showed that a cross-talk between SDF-1- and TGF-β-related signaling pathways involving phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation participated in the control of CD34+ cell cycling. We demonstrated a pivotal role of two downstream effectors of the PI3K/Akt pathway, FoxO3a and mammalian target of rapamycin, as connectors in the SDF-1-/TGF-β-induced control of the cycling/quiescence switch and proposed a model integrating a dialogue between the two molecules in cell cycle progression. Our data shed new light on the signaling pathways involved in SDF-1 cell cycle-promoting activity and suggest that the balance between SDF-1- and TGF-β-activated pathways is critical for the regulation of hematopoietic progenitor cell cycle status.

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

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