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The Hematopoietic Stem Cell in its Place
Article in Nature Immunology · May 2006
DOI: 10.1038/ni1331 · Source: PubMed
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SPECIALIZED IMMUNOLOGICAL NICHES
REVIEW
The hematopoietic stem cell in its place
Gregor B Adams & David T Scadden
A signature characteristic of stem cells is their ability to self-renew, affording a theoretically limitless ability to produce daughter
cells and their descendents. This near-timeless dimension of stem cell function is not free of the constraints of place. The idea
that highly specialized ‘microenvironmental’ cues participate in the regulation of stem cells has evidence in classic embryology
and more recently in adult stem cells through the use of model organisms. There is now ample evidence that an anatomically
defined, specifically constituted place represents the niche for hematopoietic and other tissue-specific stem cells. This
review provides a conceptual framework and detailed account of the hematopoietic stem cell niche as defined at present. The
components are assembling into a more complex view of the niche and may now be amenable to examination as a system and
possibly to alteration to affect outcomes in immune regeneration.
Stem cells modulate tissue formation, maintenance and repair based on a
complex interaction of cell-autonomous and cell-nonautonomous regulatory mechanisms. Reductionist approaches to elucidating the intrinsic
regulators of stem cell physiology have been extremely productive and
have identified many of the molecules involved. However, understanding
the extrinsic regulation of these key molecules will ultimately require the
definition of the complex microenvironments in which the stem cells
self-renew, differentiate or undergo apoptosis.
Where adult stem cells reside has only become available for study
as functional definitions of stem cells have improved. Ironically, the
hematopoietic stem cell (HSC) is well characterized by ‘immunophenotype’, yet its precise location in bone marrow has been refractory to
study mainly because this most liquid of tissues resides in the most
rigid, bone. In contrast, stem cell populations in other tissue types have
more fixed architectural positions yet have been relatively resistant to
definition partly because of their anatomical relationships. These cells
are embedded in tissues and therefore cannot be readily transplanted, a
key element in defining stem cell function. Identifying these cell types,
then, is based mostly on lineage-tracing studies and the ability of the
cells to retain dyes that are diluted with cell division. In contrast to their
more vigorously proliferative daughter cells, stem cells reside in relative quiescence, dividing infrequently and therefore retaining dye. The
positions of stem cells of the intestine, skin and brain are therefore now
characterized in location. However, insights into the regulatory functions of local cell types in the niche have been driven mainly by studies
of invertebrate systems.
Studies of gonadal tissue from Drosophila melanogaster and
Caenorhabditis elegans have permitted the definition and identification
of ancillary niche cells, physical cell-cell interactions and the molecular
Center for Regenerative Medicine, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts 02114, USA, and Harvard
Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138,
USA. Correspondence should be addressed to D.T.S.
(scadden.david@mgh.harvard.edu).
Published online 20 March 2006; doi:10.1038/ni1331
NATURE IMMUNOLOGY VOLUME 7 NUMBER 4 APRIL 2006
pathways that govern the interaction between the stem cell and its local
environment1–3. The work of several researchers studying these invertebrate systems has provided in-depth experimental evidence for a specialized environment for stem cells that was first proposed in the setting
of hematology in 1978 (ref. 4). The ideas derived from invertebrates are
along several lines and serve as guides of relevance to ‘immunohematology’: first, the number of stem cells in a niche is tightly regulated; second,
physical interaction among heterologous types of cells is important for
the maintenance of the stem cell state; third, products of the niche provide
the molecular basis for physical interactions and a balance of inhibitory
and stimulatory signals governing stem cell number and function; fourth,
niche occupancy can impose ‘stem cell–like’ characteristics on some cells
even if they are not stem cells. Each of these is discussed below.
Stem cells represent a peculiarly troublesome cell type. They are essential for the formation, maintenance and repair of tissues, yet they function simply as a root source of more mature ‘offspring’ that do the real
business of tissue function. Stem cells also represent a potential threat
to the organism, as they have such undifferentiated characteristics, have
self-renewal capabilities and can produce offspring with explosive proliferative capability. Stem cells out of balance could certainly pose a danger
to survival of the organism and, at the very least, in large numbers pose
a substantial energy drain. The idea that stem cell numbers are highly
constrained is perhaps best demonstrated in the D. melanogaster germarium, in which germline stem cells are generally restricted to two to
three cells and only rarely exceed that number5. In mammalian systems,
HSCs have been estimated to be conserved in number even between
animals of very different sizes6. Estimates of total HSCs in animals as
disparate as the mouse and cat are 1.1 × 104 cells per animal for each
species. Thus, the stem cell pool size is a governed parameter and any
efforts at expansion in vivo will probably have only modest success. The
levels of control for this parameter are probably many, and understanding them will be important for the ultimate development of stem cell
manipulation strategies.
One such level of control may be the apparent requirement for physical interaction between stem cells and their niche. In invertebrates, this
has again been well demonstrated. Disruption of the cadherin-mediated
connection between D. melanogaster female germ cell stem cells and the
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© 2006 Nature Publishing Group http://www.nature.com/natureimmunology
Osteoblast
N-cadherin
Jagged1
Angiopoietin-1
CXCL12
KL
Dkk1
Wnt
Hh
TGF-BMP
Stem cell
N-cadherin
Notch1
Tie-2
CXCR4
Stem
cell
Kit
Frizzled–LRP5,6
–LRP6
Patched
TGFR-BMPR
Osteoblast
Osteopontin
Ca2+
Ca++
CD44
VLA-4
VLA-5
CaR
Figure 1 Interactions in the endosteal niche. Hematopoietic stem cells
engage niche components (large font) through interactions that modulate
their function. For the molecular components of the niche–stem cell
interactions, black indicates definitive involvement and gray indicates
putative involvement. KL, Kit ligand; Dkk1, Dickkopf1; Wnt, wingless;
Hh, hedgehog; TFG-BMP, transforming growth factor-β family and bone
morphogenic protein family; LRP5-LRP6, lipoprotein related–receptor
proteins 5 and 6; TGFR-BMPR, transforming growth factor receptor and
bone morphogenic protein receptor; VLA, very late antigen (integrin).
niche ‘cap’ cell results in stem cell loss7. Whether that dependence is truly
due to maintenance of the junction or simply to proximity to niche cell
products is not entirely clear. However, a requirement for physical interaction with niche cells would be one effective means of limiting stem
cell numbers. It would also provide an orienting stimulus affecting cell
polarity that may be critical in determining the outcome of cell division.
For example, the relative balance between symmetric and asymmetric
cell division can greatly influence stem cell numbers and the ability of
stem cells to produce maturing daughter cells. A cell that divides with
a cleavage plane perpendicular to niche cell has the potential to have
both daughter cells remain in contact with the niche cell. In contrast, a
cleavage plane parallel to the niche cell would result in one daughter cell
at a distance from the niche cell. These distinct localizing features may
be envisioned as resulting in either two niche-bound stem cells (symmetric cell division) or one daughter cell at a distance from the niche,
enabling a differentiation program, while the other remains at the niche
(asymmetric division yielding one maturing cell and one stem cell). Such
polar organization now has empiric support in D. melanogaster, in which
changing the stem cell cleavage orientation by modifying the adenomatous polyposis coli tumor suppressor protein considerably alters the
number of stem cells8. Whether the same is true for mammalian systems
has not been well defined, but it is now apparent that N-cadherin is present at the interface of some stem cells and niche cells9,10.
Other regulatory dimensions of the niche are still being explored, but
molecular interactions in one system often provide insight into another.
Detailed analyses of male and female D. melanogaster gonads initially
demonstrated distinct signaling pathways. A Janus kinase–signal transducer and activator of transcription (Jak–STAT) pathway identified as
crucial for male germ stem cell regulation was thought to be distinctive
to the male and not present in the ovary. However, data now indicate
otherwise; there are common Jak–STAT signaling pathways in both germ
stem cells11. Similarly, Notch pathway activation is important in maintaining germ stem cells in C. elegans and has also been linked to the HSC
niche in mice12,13. Therefore, the rules, pathways and perhaps structural
components of invertebrate stem cell niches may provide opportunities
for accelerating the exploration and understanding of how the specialized microenvironment can affect mammalian stem cells.
334
Finally, the invertebrate system offers one note of caution that must
be explored in mammalian niches. Niche structures have the potential
to determine stem cell state and not just be supportive. For example,
studies have shown that a vacant niche can remain viable and that
other cell types may engage the niche, with a resultant change in phenotype. Depending on the specific system, it seems that non–stem cells
can acquire either a more proliferative phenotype or frankly revert to a
stem cell–like, less differentiated state14,15. That finding or idea raises the
‘power’ of the niche to another plane, suggesting that it may participate
actively in imposing stem cell–like characteristics even on ectopic cells of
different phenotype. An intriguing possibility is then posed: if the same
holds true in mammals, the niche may be capable of contributing to
abnormal tissue regulation, possibly ‘encouraging’ aberrant or malignant
cells by providing ‘stem-like’ features to a more mature cell type.
HSC interactions with specialized microenvironments
In the mammalian organism, one of the most extensively studied stem
cells is that of the hematopoietic system. In mice, HSCs first arise in the
yolk sac and produce embryonic hemoglobin containing red blood cells
at embryonic day 7 (E7), followed by a second wave of erythromyeloid
cell production from the yolk sac at E8.25 (ref. 16). In the embryo proper
of the mouse, the aorto-gonadal-mesonephros and placental regions of
the developing embryo begin production of definitive hematopoietic
cells at around E10.5 (refs. 17,18). The liver is then ‘invested’ with stem
cells to become the main source of hematopoiesis until approximately
the second trimester, when the HSCs are thought to translocate via the
peripheral circulation to the bone cavities to form the bone marrow. The
peripatetic developmental history of HSCs does not stop with arrival
in the marrow space. Instead, it seems that these cells undergo regular
trafficking into and out of the bone, spending brief intervals in the circulation. In mice whose peripheral circulation is joined, it has been shown
that HSC residence time in the circulation is less than 6 seconds for more
than 99% of the cells19. As approximately 100–400 cells are present in the
circulation at a given time, many stem cells transit through the circulation daily. It is not apparent that they all necessarily encounter a specific
niche along the way or that those circulating are the same as those that
spend time in the bone marrow. These caveats notwithstanding, it is
reasonable to conclude that stem cells, although regulated by place, are
not static in a given space. They seem to be in motion, and imaging of
primitive cells ex vivo has indicated that indeed they have highly dynamic
membrane extensions and rapid motility20. Although mature cells of the
immune system may be viewed as using motility as a needed feature of
surveillance in host defense, it is less teleologically intuitive to understand these phenomena in stem cells. Is there some monitoring function
they provide? It is not at all apparent, although bone marrow–derived
cells do incorporate into neovascular sites, suggesting that some involvement in repair at a distance is possible21. This frequent trafficking is a
process that is presumably recapitulated in kind during the intravenous
delivery of stem cells during transplantation therapy. Cells moving on
and off niche sites may the basis for the engraftment of infused stem
cells that can occur with low frequency even without cytotoxic ‘emptying’ of the niche22.
The movement of HSCs to bone marrow occurs early in bone formation. The cartilaginous anlage of bone initially becomes infiltrated
by vessels and, with them, cartilage-consuming phagocytic cells called
chondroclasts. Osteoblasts arrive, but the arrival of HSCs occurs only
after mineralization of extracellular matrix laid down by osteoblasts
is initiated. This combined presence of osteoblasts and mineral in the
developing bone at the time hematopoiesis shifts to bone marrow
suggests the many components of bone contributing to bone marrow
regulation that have since been demonstrated.
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REVIEW
Although bone marrow has been a recognized site of blood cell production for decades, what bone does for bone marrow has been less
clear. Simple bone marrow histology demonstrated an admixture of
differentiating hematopoietic cells in spaces bounded by trabecular
bone, endothelium-lined sinuses, feeder vessels and adipocytes. Regional
clustering in grape-like arrangement of red cell precursors, in particular
at the trabecular interface, suggests a more complex anatomic organization. However, studies of primitive cells labeled ex vivo and tracked
in vivo have demonstrated the endosteal localization of HSCs23. Those
studies, coupled with in vitro coculture studies indicating the ability of
osteoblastic cells to secrete cytokines and support primitive blood cells
ex vivo, have set the stage for more focused analysis of the interaction
between bone and bone marrow24,25.
What bone does for bone marrow
Distinguishing bone from other mesenchymal tissues are several key
features: a unique mesenchymal cell type (the osteoblast), distinctive
extracellular matrix glycoproteins and a uniquely rich mineral content of high density calcium salts. Each of these components has now
been shown to participate in a regulatory microenvironment for HSCs.
In aggregate cells, matrix and mineral contribute to a unique
microenvironment or niche.
Three main lines of evidence have indicated involvement of the osteoblast. The first two were concurrent studies examining genetic models
that modified osteoblasts, showing that they secondarily affect HSCs.
One group, studying bone morphogenetic protein signaling, created a
conditional knockout of the bone morphogenetic protein 1a receptor
that caused a bony defect, increasing the number of osteoblasts9. HSC
numbers were proportionately increased and were found to be localized
in immediate proximity to spindle-shaped osteoblasts, forming what
seemed to be a homotypic junction associated with N-cadherin. Taking a
different tack, the second group targeted the osteoblast specifically using
a transgenic mouse with a constitutively active parathyroid hormone
receptor driven by the osteoblast-specific 2.3-kilobase fragment of the
promoter of the gene encoding procollagen, type I, α1. The resulting
mouse had increased trabecular bone and increased numbers of HSCs13.
The increase in primitive cell support was associated with increased
expression of the Notch ligand Jagged1, and increased Notch1 activation
that could be blocked by γ-secretase inhibition, suggesting involvement
of that pathway in the ‘upmodulation’ of stem cells with osteoblast stimulation. Jagged1-deficient mice have normal hematopoiesis, so the effect
may be obtained only with osteoblast stimulation and may not participate in homeostatic regulation of stem cells at the endosteal niche26.
The third piece of evidence for involvement of the osteoblast has been
provided by a study with selective depletion of osteoblasts in vivo due
to a transgene construct of the gene encoding herpes simplex virus thymidine kinase under the control of an osteoblast-specific promoter27.
Exposure of the mice to ganciclovir, because of expression of the herpes
simplex virus thymidine kinase cassette, selectively induces metabolic
death of osteoblasts and a subsequent decrease in hematopoietic capacity. Therefore, the osteoblast is a cell participant in the stem cell niche
providing regulatory cues for the maintenance of hematopoiesis.
Although the osteoblast is a cellular component of the niche, the products of the osteoblast that participate in the regulatory microenvironment
for stem cells are known in only limited detail. Interaction of angiopoietin
1 at the osteoblast surface with Tie-2 on stem cells is important for maintaining stem cell quiescence in the niche10 (Fig. 1). Those data have identified a set of molecular interactions in the niche that are probably just the
beginning of a host of previously underappreciated pathways creating a
synaptic-like interface. Candidates being studied are those of the wingless, hedgehog, bone-morphogenetic protein, Kit ligand and chemokine
NATURE IMMUNOLOGY VOLUME 7 NUMBER 4 APRIL 2006
stromal cell–derived factor 1 (also called CXCL12) pathways (Fig. 1), but
those are based on candidate gene approaches, and more global analyses
will probably yield many others not predicted at present. Unanticipated
interactions are perhaps best exemplified by the identification of involvement of adrenergic signaling in altering osteoblast function, reducing
CXCL12 production and thereby leading to stem cell release into the
circulation28. The demonstration that adrenergic signaling may alter the
niche raises another important issue.
The interface of the osteoblast and stem cell is probably rich in
molecular interactions that guide the response of stem cells to specific
physiological conditions. The niche may be the focal point for changes
in the state of tissues that result in a change in the regenerative processes
rooted in stem cell activity. Exactly how the niche integrates signals of
tissue state is unclear, but neural input does seem to be one possibility,
as does systemic cytokine or hormone activity13,28,29. Divergent processes may come to bear on the niche–stem cell interface. One study
has shown that intra–stem cell changes in c-Myc concentrations alter
molecular interactions at the niche, including N-cadherin expression,
and are associated with aberrant accumulation of stem cells30. A perturbation in the regulation of stem cell number and function at the
level of molecular interactions in the niche might participate in the
pathophysiology of bone marrow failure or hyperproliferation states.
Conversely, these interactions may offer a therapeutic opportunity to
manipulate stem cells.
In addition to the mesenchymal cell types that distinguish bone, it
also has a unique mix of extracellular matrix components. Osteopontin
has been studied particularly closely because of its known involvement
in other hematological settings. In particular, osteopontin is important
in mature immune cell function, serving as a mediator of T helper type
1 and 2 ‘choice’, cell growth and localization. Osteopontin is useful for
assessing in bone marrow function in part because of its cytokine and
adhesion characteristics in those other settings, but also because it is a
modulated product of osteoblasts and binds to cell surface receptors on
HSCs, CD44 and the α4 and α5β1 integrins31 (Fig. 1). Two studies have
used osteopontin-null mice to demonstrate that there is a stem cell–nonautonomous function for osteopontin in regulating stem cells in the
niche32,33. Notably, an absence of osteopontin results in an increase in
the number of HSCs, by a stem cell–nonautonomous or microenvironment-dependent mechanism. Those studies have shown not only that
many factors, including apoptosis and cell cycling, may contribute to the
increase in stem cell number but also that when activated osteoblasts are
in the niche and osteopontin is not, the population expansion of stem
cells is ‘superphysiological’. Thus, osteopontin may be a constraining
factor on stem cell number and perhaps may restrict the number of stem
cells that can result from niche activation.
The mineral content of bone is an obviously distinctive characteristic
distinguishing it from other mesenchymal tissues. Classic physiological
experiments have measured quantities of ionic calcium in tissues and
have defined that although the Ca2+ concentration is generally rigidly
maintained in most extracellular spaces, at sites of injury or inflammation and at the surface of remodeling bone, the concentration can vary
upward by more than an order of magnitude34. It is then reasonable to
question whether this simple ionic gradient could provide the basis for
hematopoiesis in mineralized tissue. Extracellular Ca2+ concentrations
are recognized by the seven-transmembrane calcium-sensing receptor
and can result in an intracellular G protein–coupled response35. That
receptor is on hematopoietic cells and has been identified on the surface
of HSCs36. In mice deficient in that receptor, HSCs form normally in the
fetal liver but do not engraft in the bone marrow. Hematopoiesis in sites
such as the spleen (important in mouse but not in normal adult human
hematopoiesis) occurs, but the cells are unable to engage the endosteal sur-
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© 2006 Nature Publishing Group http://www.nature.com/natureimmunology
face of bone or to successfully engraft in bone marrow. The effect is stem
cell autonomous, and transplantation into wild-type mice with normal
calcium homeostasis does not alter the phenotype. Therefore, the ability
of stem cells to sense and respond to the increased calcium concentrations
at the endosteal surface participates in creating the unique stem cell-niche
interaction that enables bone marrow hematopoiesis.
Multiple niches for the HSC
The finding that HSCs without the calcium-sensing receptor can engraft
in extramedullary spaces and foster blood cell production strongly suggests that regions other than the endosteal surface can function as a stem
cell niche, at least in the mouse. Similar conclusions might be drawn
from studies of mice with bony defects in which either an osteopetrotic
or defective bony phenotype is associated with extramedullary hematopoiesis. For example, Runx2 is an osteoblast-associated transcription
factor without which ossified bone does not form37. Yet hematopoiesis
continues even after the developmental shift to bone marrow would
normally occur. Cell production is abnormal, but hematopoiesis is
ongoing. Similarly, a mouse with osteopetrosis due to deficiency in the
macrophage-colony stimulating factor receptor has altered hematopoiesis with extramedullary sites involved38. One site known to support
hematopoiesis in mice and in certain disease conditions in humans is
the spleen. This richly vascularized tissue is still relatively unexplored
territory in terms of specific niche definition. In contrast, perivascular
tissue in bone marrow now seems to be a potential niche site.
Label retention is a mode of imaging stem cells that has been applied
to hematopoietic as well as nonhematopoietic tissues. With that strategy, the endosteal surface has been identified histologically as a site for
quiescent stem cell localization9. The alternative of antigen labeling
was not successful on histological sections until the identification of
the labeling of long-term repopulating HSCs by members of the signaling lymphocyte activation molecule family (specifically CD150)39.
Immunohistochemistry has been used to find CD150+ cells in close
proximity to the endothelially lined vascular tissue, a site that has been
noted as a regulatory zone for megakaryocyte progenitors40. The CD150+
HSCs were notably more abundant in this area than at the endosteal
zone, where only approximately 14% of labeled cells could be found. The
one caveat to those studies is that where cells reside may not be equivalent to a functional niche. The perivascular space has been hypothesized
as being a site where more mitotically active stem cells may be located,
and perhaps that is why it has not been identified in label-retaining
assays in bone marrow. However, whether the perivascular region is
simply a ‘way station’ en route to intravascular trafficking, a repository
for stem cells or a true regulatory niche remains to be determined.
Other data analyzing the bone marrow microvasculature from a different perspective, however, have provided some support for the idea of
a perivascular niche. In experiments attempting to elucidate the mechanisms for localizing primitive populations of cells in bone marrow,
hematopoietic tumor cell lines have been used in conjunction with highresolution video confocal microscopy41. Those data have shown that cells
in the circulation home to specific regions of microvessels and traffic into
the perivascular space. The homing site has been characterized by regional
expression of the chemokine CXCL12, and homing to those microdomains is blocked by downregulation or pharmacological blocking of the
CXCL12 receptor CXCR4. Those same zones are used by primitive primary hematopoietic cells and are the site where cells labeled ex vivo were
found to be resident for at least 60 days, retaining label. Those data do not
conclusively demonstrate that the perivascular region is a regulatory stem
cell niche; however, they are consistent with the idea that primitive cells not
only localize to the perivascular space but also undergo slow cell division.
Therefore, there may be highly specialized microvascular as well as osteo-
336
blastic niches in the bone marrow that participate in hematopoiesis. The
distinctions between these sites is probably important functionally, but
can only be hypothesized at this time. Ultimately, it will be highly informative to image HSCs and thereby determine if they move between the
perivascular or endosteal sites or if these represent distinctive homes for
different subset of cells. It will be useful to determine which population is
mobilized in strategies used clinically to get stem cells into the circulation.
Finally, it will also be useful to determine whether in settings of disease
these niches have different functions; specifically, whether neoplastic cells
have different responsiveness to one niche versus another.
Niche modeling
As the niche is an idea with increasing dimension as parts are defined,
the potential to exploit that information therapeutically is coming into
focus. There may be several ways in which that may occur. Perhaps the
individual components function only in the context of an integrated system, but are studied alone. As distinct parts are identified, the potential to
reorganize them ex vivo to enable more controlled, in-depth analysis of
the system may become possible. This could be envisioned as including
several lines of enquiry, such as examination of the physical relationships
needed in the niche, direct measurement of symmetric versus asymmetric division in the niche and the potential to do ‘chemical screening’
to alter the niche. Furthermore, the niche components begin to be seen
as potential contributors to states of stem cell dysfunction. That could
happen in the setting of acquired marrow failure or in dysplastic and
neoplastic states. It is now becoming possible to examine whether the
normal stem cell niche is similar to that of the leukemic stem cell, for
example. Does altering the niche change the relative support of normal
versus abnormal stem cells? Can the niche become a target that can be
manipulated to change the balance of competition in the marrow that
accompanies diseases such as leukemia and myelodysplasia?
Recognition of the niche components affords the possibility of targeting those components to affect stem cell function in settings of clinical
relevance. In particular, the identification of the osteoblast as a niche
participant suggests that agents developed to target the osteoblast in
context of bone disorders such as osteoporosis may be re-examined as
possible modifiers of HSC physiology. One example of this is a mouse
bone marrow transplant model in which the recipients are treated with
parathyroid hormone to affect osteoblast number and function13. The
resulting increase in stem cells in homeostatic conditions is only twofold.
However, in conditions of stress, in which irradiated murine recipients are transplanted with limiting numbers of stem cells, stimulating
the recipient with parathyroid hormone injections generates greatly
improved survival statistics and much increased bone marrow cellularity. Whether using parathyroid hormone to improve transplant outcome
can be recapitulated in human patients is unclear, but at least one multicenter clinical study has been initiated based on those data. Therefore,
knowledge of the niche may be relevant for modifying stem cell outcomes clinically. Knowing stem cells in their place may help stem cells
achieve a more prominent position in the clinical armamentarium.
ACKNOWLEDGMENTS
We thank C. Shambaugh for administrative assistance. Supported in part by the
National Institutes of Health (HL081030 and HL44851), the Burroughs Wellcome
Fund and the Leukemia & Lymphoma Society.
COMPETING INTERESTS STATEMENT
The authors declare competing financial interests (see the Nature Immunology
website for details).
Published online at http://www.nature.com/natureimmunology/
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