Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells.
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.
Yamazaki
Satoshi
S
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Iwama
Atsushi
A
Takayanagi
Shin-ichiro
S
Morita
Yohei
Y
Eto
Koji
K
Ema
Hideo
H
Nakauchi
Hiromitsu
H
D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000254:growth & development; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D013234:Stem Cells
D016207:Cytokines