Journal
BLOOD
Volume 113, Issue 6, Pages 1250-1256Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-04-146480
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Funding
- Ministry of Education, Culture, Sport, Science and Technology, Japan, Japan Science and Technology Corporation (JST)
- Naito Foundation (Tokyo, Japan)
- Terumo Lifescience Foundation (Kanagawa, Japan)
- Grants-in-Aid for Scientific Research [21390321] Funding Source: KAKEN
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Hematopoietic stem cells (HSCs) reside in a bone marrow niche in a nondividing state from which they occasionally are aroused to undergo cell division. Yet, the mechanism underlying this unique feature remains largely unknown. We have recently shown that freshly isolated CD34(-)KSL hematopoietic stem cells (HSCs) in a hibernation state exhibit inhibited lipid raft clustering. Lipid raft clustering induced by cytokines is essential for HSCs to augment cytokine signals to the level enough to re-enter the cell cycle. Here we screened candidate niche signals that inhibit lipid raft clustering, and identified that transforming growth factor-beta (TGF-beta) efficiently inhibits cytokine-mediated lipid raft clustering and induces HSC hibernation ex vivo. Smad2 and Smad3, the signaling molecules directly downstream from and activated by TGF-beta receptors were specifically activated in CD34(-)KSL HSCs in a hibernation state, but not in cycling CD34(-)KSL progenitors. These data uncover a critical role for TGF-beta as a candidate niche signal in the control of HSC hibernation and provide TGF-beta as a novel tool for ex vivo modeling of the HSC niche. (Blood. 2009; 113: 1250-1256)
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