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Blood, 5 February 2009, Vol. 113, No. 6, pp. 1208.
Is TGF-β a stemness regulator?LUND UNIVERSITY
In this issue of Blood, Yamazaki and colleagues show that TGF-β inhibits cytokine-mediated LRC clustering in purified HSCs freshly isolated from the bone marrow and induces hibernation of HSCs ex vivo. Since cytokine stimulation of LRC is important to stimulate proliferation of HSCs, the authors propose that TGF-β may be a hibernation/quiescence regulator in the HSC bone marrow niche.
Here, Yamazaki et al use elegant techniques to examine cell signaling and behavior of single purified HSCs. The same group has recently demonstrated that cytokines (thrombopoietin and stem cell factor) induce lipid raft clustering (LRC) in purified HSCs leading to augmented cytokine signals to mediate cell-cycle entry and proliferation.4 In the present paper, single, pure HSCs (LSK CD34– cells) were examined with respect to lipid raft clustering, activation of signaling pathways, and potential to proliferate, differentiate and repopulate irradiated recipients. In the presence of stem cell factor and thrombopoietin, TGF-β could inhibit lipid raft clustering and activate phosphorylation of Smad2/3, the intracellular transducers downstream of the TGF-β receptor, in freshly isolated purified HSCs. The authors suggest that these findings indicate that TGF-β signaling is active in the bone marrow niche to keep the HSCs in hibernation (quiescent). A potent negative regulator of HSCs, p57, was found to be up-regulated following TGF-β stimulation in vitro, and single purified HSCs grown in SCF, TPO, and TGF-β for 5 days could repopulate irradiated recipients. This was impossible without TGF-β stimulation. This demonstrates that genuine HSCs were being examined. Is TGF-β an important regulator of HSCs in the bone marrow niche to mediate hibernation/quiescence and to maintain intact stemness properties, as Yamazaki and colleagues would like to suggest? All the signaling studies of the purified HSC, while elegant, are done in vitro and can only indirectly imply what is happening in vivo in the stem cell niche. Earlier studies show that HSC s deficient in ALK5 (and thereby TGF-β signaling) have normal self-renewal, repopulation capacity, and differentiation potential in vivo, indicating that TGF-β is not an important regulator of hibernation/quiescence/stemness in vivo.2 Therefore, the 2 studies appear to present conflicting findings. However, both hypotheses may be correct. It is possible that TGF-β regulates quiescence/hibernation in the bone marrow niche. But this role may be redundant because there are many other regulators and signals to preserve stemness of the HSCs in the niche and the removal of one may not lead to an observable phenotype. Another possible explanation could be that studies with the TGF-β signaling deficient mice were performed after bone marrow transplantation,2 and this experimental setting following the hematopoietic stress of the transplantation procedure may not be optimal for studying the regulation of hibernation/quiescence. It is challenging to look at regulation of individual HSCs in the bone marrow niche, but new techniques and future experimental approaches may be able to reveal whether TGF-β regulates quiescence/hibernation/stemness of HSCs in the niche.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
