title: 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.
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-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Chabanon
authors.forename: Christophe
authors.initials: C
authors.lastname: Desterke
authors.forename: Emilie
authors.initials: E
authors.lastname: Rodenburger
authors.forename: Denis
authors.initials: D
authors.lastname: Clay
authors.forename: Bernadette
authors.initials: B
authors.lastname: Guerton
authors.forename: Laetitia
authors.initials: L
authors.lastname: Boutin
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.forename: Olivier
authors.initials: O
authors.lastname: Pierre-Louis
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
authors.forename: Lucile
authors.initials: L
authors.lastname: Abecassis
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Bourgeade
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lataillade
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Le Bousse-Kerdilès