Sci. STKE, 22 August 2006
HEMATOPOIESIS Waking Stem Cells
Hematopoietic stem cells (HSCs) reside in bone marrow in a nondividing state from which they are occasionally roused to enter the cell cycle. Noting the similarity of HSC dormancy to mammalian hibernation and Caenorhabditis elegans dauer formation, Yamazaki et al. wondered whether the PI3K (phosphatidylinositol 3-kinase)-Akt-FOXO signaling pathway, implicated in regulation of both of these states, might be involved in HSC "hibernation." In quiescent CD34– Kit+ Sca-1+ lineage marker-negative (CD34– KSL) cells freshly isolated from mouse bone marrow, no phosphorylated (activated) Akt was apparent, and its downstream target FOXO3a was found in the nucleus. In contrast, Akt was phosphorylated and FOXO3a was present in the cytoplasm of cycling CD34+ KSL progenitor cells. Cytokine treatment of CD34– KSL cells led to polarization of the lipid raft marker GM1 ganglioside as well as phosphorylation of Akt and relocation of FOXO3a to the cytoplasm. Depleting cholesterol with β-cyclodextrin (MβCD) to inhibit lipid raft clustering in response to cytokine treatment in CD34– KSL cells suppressed Akt activation and FOXO3a relocation; inhibited cytokine-dependent translocation of cyclins D1, D2, and D3 to the nucleus; and prevented disappearance from the cytoplasm of the cyclin-dependent kinase inhibitor p57Kip2. When single HSCs that had survived without dividing for several days in the presence of MβCD, stem cell factor, and thrombopoietin were placed in MβCD-free medium containing stem cell factor, thrombopoietin, interleukin-3, and erythropoietin, they retained the ability to proliferate and differentiate along various myeloid lineages in vitro and to repopulate the hematopoietic system of lethally irradiated mice. Thus, the authors conclude that lipid raft clustering plays a key role in HSC emergence from dormancy and that the signaling pathway involved in mediating HSC hibernation resembles that involved in dauer formation.
S. Yamazaki, A. Iwama, S. Takayanagi, Y. Morita, K. Eto, H. Ema, H. Nakauchi, Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 25, 3515-3523 (2006). [PubMed]
Citation: Waking Stem Cells. Sci. STKE 2006, tw283 (2006).
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