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TISSUE-SPECIFIC STEM CELLS

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

^aInstitut National de la Santé et de la Recherche Médicale, U602, Villejuif, France;
^bUniversity of Paris-Sud, Institut André Lwoff, Villejuif, France;
^cIFR89, University of Paris-Sud, Institut André Lwoff, Villejuif, France;
^dCentre de Transfusion Sanguine des Armées, Hôpital Percy, Clamart, France;
^eInstitut National de la Santé et de la Recherche Médicale, U790, Villejuif, France;
^fInstitut National de la Santé et de la Recherche Médicale, U542, Villejuif, France

Key Words. SDF-1 • TGF-β • FoxO3a • mTOR • CD34⁺ progenitors • Cell cycle

Correspondence: 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; e-mail: caroline.le-bousse-kerdiles{at}inserm.fr; or 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; e-mail: jjlataillade{at}ctsa-armees.fr

Received on March 3, 2008; accepted for publication on August 16, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

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.