Putting Hematopoietic Stem Cells to Sleep
Published on: March 01, 2012
Dr. Kurre indicated no relevant conflicts of interest.
Yamazaki S, Ema H, Karlsson G, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147:1146-1158.
Homeostatic maintenance of organ integrity and regenerative recovery frominjury rely on tissue stem cells that integrate proliferative cues with those that arise as a result of cell damage. For the blood and immune systems, bone marrow hematopoietic stem cells (HSCs) provide the plasticity necessary to achieve this dynamic equilibrium. Disturbing the carefully calibrated balance between self renewal, differentiation, and apoptosis can promote leukemogenesis or, alternatively, lead to bone marrow failure. Presumably, to ensure organ function for the lifespan of the host, most stem cells appear to be quiescent (G0 cell cycle status) at any given time, residing in low-oxygen niches and exhibiting markedly reduced metabolic activity. Together, cell-autonomous mechanisms and microenvironmental signals regulate the stochastic activation of individual stem cells to maintain routine organ function and activate larger numbers of HSCs during times of increased demand.1 A wide range of stimuli (e.g., blood loss, ionizing radiation exposure, chemotherapy, mobilization for HSC donation) provoke cell cycle entry and asymmetric cell division to maintain the HSC pool size and produce primitive progenitors destined for differentiation. Work by many groups over the past decade has revealed a host of cellular and molecular factors that contribute to this carefully orchestrated process.2 In contrast, the return of HSCs to dormancy has long been viewed as an unregulated, default fate that follows after cessation of the proliferative/differentiation stimulus. Recent work by Yamazaki and colleagues, however, appears to have revealed the cellular and molecular switch that returns HSCs to “hibernation.” The authors had previously identified transforming growth factor beta (TGF-β) as a key regulatory molecule involved in HSC quiescence. The current work followed up on an unresolved issue from those earlier studies, namely how complexed, latent TGF-β might be rendered functional for signaling to HSC. Using a murine model, the investigators unexpectedly discovered a crucial role for glial cells in the signaling process.They tracked nerve fibers from non-myelinating Schwann cells alongside blood vessels and found these cells to be unique producers of active TGF-β. Even though the mechanism of release of TGF-β from its inactive precursor complex was not conclusively resolved, the investigators demonstrated the close physical proximity of Schwann cells to HSCs in the bone marrow and showed the expression by Schwann cells of several genes encoding factors known to support HSC niche function. Convincingly, denervation resulted in successive loss of active TGF-β, depletion of quiescent HSCs, and quantitative exhaustion of the stem cell pool, without qualitatively affecting the remaining HSCs. Related work in a recent issue of Cell Stem Cell 3,4 supports the present report and provides the molecular fine print for the process by identifying p57 and p27 as key mediators of HSC dormancy. Together, these studies suggest that hibernation is an actively regulated, indispensible feature of long-lived HSCs that is an essential component of homeostasis of the hematopoietic system.
The investigators have identified a key mechanism by which HSCs return to dormancy and revealed the role of quiescence in preserving HSC pool size and bone marrow function. The work furthers our understanding of the remarkable role that the nervous system plays in hematopoiesis. Future studies should provide insight into the precise mechanism by which proteolytic cleavage of latent TGF-β is locally orchestrated. Understanding regulation of dormancy may illuminate mechanisms of bone failure and suggest novel approaches to overcoming the chemotherapeutic resistance of leukemic stem cells.2
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- Lo Celso C, Scadden DT. The hematopoietic stem cell niche at a glance. J Cell Sci. 2011;124:3529-3535.
- Trumpp A, Essers M, Wilson A. Awakening dormant haematopoietic stem cells. Nat Rev Immunol. 2010;10:201-209.
- Matsumoto A, Takeishi S, Kanie T, et al. p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell. 2011; 9:262-271.
- Zou P, Yoshihara H, Hosokawa K, et al. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell. 2011;9:247-261.