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

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.