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Waking Stem Cells

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Science  01 Sep 2006:
Vol. 313, Issue 5791, pp. 1205
DOI: 10.1126/science.313.5791.1205c

Hematopoietic stem cells (HSCs) reside in bone marrow in a nondividing state from which they can be roused to enter the cell cycle. Noting the similarity of HSC dormancy to mammalian hibernation and Caenorhabditis elegans dauer formation, Yamazaki et al. looked at the PI3K (phosphatidylinositol 3-kinase)-Akt-FOXO signaling pathway. In quiescent 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, phosphorylated Akt and FOXO3a were found in the cytoplasm of cycling progenitor cells. Cytokine treatment of quiescent 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 (MßCD) in order to inhibit lipid raft clustering suppressed Akt activation and FOXO3a relocation. When single HSCs that had survived without dividing for several days in the presence of MßCD, stem cell factor, and thrombopoietin were placed in MßCD-free medium, they proliferated and differentiated along various myeloid lineages in vitro and could repopulate the hematopoietic system of lethally irradiated mice. Thus, lipid raft clustering may mediate HSC emergence from dormancy via signaling pathways resembling those involved in the dauer stage. — EMA

EMBO J. 25, 3515 (2006).

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