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

作者：Chabanon Aurelie; Desterke Christophe; Rodenburger Emilie; Clay Denis; Guerton Bernadette; Boutin Laetitia; Bennaceur Griscelli Annelise; Pierre Louis Olivier; Uzan Georges; Abecassis Lucile; Bourgeade Marie Francoise; Lataillade Jean Jacques; Le Bousse Kerdiles Marie Caroline^*

来源：Stem Cells, 2008, 26(12): 3150-3161.

DOI：10.1634/stemcells.2008-0219

• SDF-1
• TGF-beta
• FoxO3a
• mTOR
• CD34(+) progenitors
• Cell cycle

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-beta (TGF-beta),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-beta target genes, confirming its cell cycle-promoting effect. We showed that a cross-talk between SDF-1- and TGF-beta-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-beta-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-beta-activated pathways is critical for the regulation of hematopoietic progenitor cell cycle status. STEM CELLS 2008; 26: 3150-3161

• 出版日期2008