Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells

• DOI: 10.1038/sj.emboj.7601236
• Publication Date: 2006-07-20T14:04:28Z
• Authors: Satoshi Yamazaki; Atsushi Iwama; Shin-ichiro Takay...; Yohei Morita; Koji Eto; Hideo Ema; Hiromitsu Nakauchi
• Keywords: 0301 basic medicine; Stem Cells; Cell Cycle; Fluorescent Antibody Technique; Apoptosis; Hematopoietic Stem Cells; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Membrane Microdomains; Animals; Cytokines; Caenorhabditis elegans; Cells, Cultured; Signal Transduction

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche in a noncycling state and enter the cell cycle at long intervals. However, little is known about inter- and intracellular signaling mechanisms underlying this unique property of HSCs. Here, we show that lipid raft clustering is a key event in the regulation of HSC dormancy. Freshly isolated HSCs from the BM niche lack lipid raft clustering, exhibit repression of the AKT-FOXO signaling pathway, and express abundant p57(Kip2) cyclin-dependent kinase inhibitor. Lipid raft clustering induced by cytokines is essential for HSC re-entry into the cell cycle. Conversely, inhibition of lipid raft clustering caused sustained nuclear accumulation of FOXO transcription factors and induced HSC hibernation ex vivo. These data establish a critical role for lipid rafts in regulating the cell cycle, the survival, and the entry into apoptosis of HSCs and uncover a striking similarity in HSC hibernation and Caenorhabditis elegans dauer formation.