Submitted April 7, 2008
Accepted July 27, 2008
TGF-
as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation
Satoshi Yamazaki, Atsushi Iwama, Shin-ichiro Takayanagi, Koji Eto, Hideo Ema, and Hiromitsu Nakauchi*
ReproCELL Inc., Tokyo, Japan
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
JST, ERATO, Sanbacho, Chiyoda-ku, Tokyo, Japan
* Corresponding author; email: nakauchi{at}ims.u-tokyo.ac.jp.
Hematopoietic stem cells (HSCs) reside in a bone marrow niche in a non-dividing 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-
(TGF-) 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- 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- as a candidate niche signal in the control of HSC hibernation and provide TGF- as a novel tool for ex vivo modeling of the HSC niche.
