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Review Series
HEMATOPOIETIC STEM CELLS

Making sense of hematopoietic stem cell niches

Philip E. Boulais1,2 and Paul S. Frenette1-3
1

Department of Cell Biology, 2The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, and 3Department of
Medicine, Albert Einstein College of Medicine, Bronx, NY

The hematopoietic stem cell (HSC) niche

commonly refers to the pairing of hematopoietic and mesenchymal cell populations
that regulate HSC self-renewal, differentiation, and proliferation. Anatomic localization of the niche is a dynamic unit from the
developmental stage that allows proliferating HSCs to expand before they reach the

bone marrow where they adopt a quiescent

phenotype that protects their integrity and
functions. Recent studies have sought to
clarify the complexity behind the HSC niche
by assessing the contributions of specific
cell populations to HSC maintenance. In
particular, perivascular microenvironments
in the bone marrow confer distinct vascular

niches that regulate HSC quiescence and

the supply of lineage-committed progenitors. Here, we review recent data on the
cellular constituents and molecular mechanisms involved in the communication
between HSCs and putative niches. (Blood.
2015;125(17):2621-2629)

The origins of hematopoiesis

The hematopoietic system supplies our body with .100 billion mature
blood cells every day that carry out functions such as oxygen transport,
immunity, and tissue remodeling. Hematopoietic stem cells (HSCs),
located at the top of the hematopoietic hierarchy, are responsible for
replenishing our pool of blood cells throughout life. Early work by
James Till and Ernest McCulloch provided evidence that single bone
marrow cells could give rise to multilineage progenitors1,2 and could
undergo at least short-term self-renewal.3 These studies paved the way
to the conceptual hierarchy in HSC differentiation and the role of HSCs
in the maintenance of hematopoietic homeostasis. Whether and how
HSCs could autonomously modulate their function or be inuenced
by extrinsic factors, however, has remained poorly understood until
recently. In the adult stage, most HSCs are found in a quiescent state
that protects them from genotoxic insults and ensures their long-term
repopulating ability.4-6 The state and function of HSCs must be nely
tuned to protect their self-renewal capacity and prevent their exhaustion, which is crucial for blood system homeostasis. Differences in
spatial localization of colony-forming unit, spleen, within rodent long
bones is associated with a discrete proliferative state, which suggests
that specic microenvironments within the bone marrow can regulate
the state and function of hematopoietic stem and progenitor cells
(HSPCs).7 Bone marrow stromal cells promote ex vivo proliferation
and differentiation of HSPCs in long-term cultures, supporting the
notion that microenvironmental cues may inuence the fate of HSCs
and modulate hematopoiesis.8 This idea is crystalized by the niche
hypothesis, in which the niche forms a regulatory unit that limits
the entry of HSCs into the cell cycle, thereby protecting them from
exhaustion or from errors in DNA replication.9 Therefore, identication
of molecular cues that regulate the fate of HSCs will improve our
knowledge of the regulation of hematopoiesis in health and disease.
During development, HSCs trafc between niches in order to establish hematopoiesis. Primitive hematopoiesis takes place in the yolk
sac approximately on embryonic day 7.0 (E7.0) when immature precursors give rise to erythrocytes that will supply oxygen to the developing

embryo.10 The presence of the rst denitive HSC known to be able

to fully reconstitute the hematopoietic system upon transplantation is
found in the aorta-gonad-mesonephros in mice and humans.11,12
However, some studies have suggested that yolk sac cells from E9.0
to E10.0 can mature into denitive HSCs when transplanted into
a newborn rather than an adult mouse.13,14 In addition, the placenta
represents a signicant reservoir of HSCs during development.15,16
Once the vasculature is developed, HSCs migrate to the fetal liver
on or near E12.0 where they expand and differentiate.10 Fetal liver
HSCs are actively cycling in contrast to their bone marrow counterparts
and can also outcompete adult bone marrow HSCs when transplanted
into irradiated recipients.17 During HSC expansion in the fetal liver,
chondrocytes and osteoblasts are produced within mesenchymal condensations to create cartilage and bone.10 Skeletal remodeling is associated with bone vascularization, which allows homing of HSCs and
colonization of the fetal bone marrow by E17.5.10 This process is
mediated through CXCL12 production by bone marrow stromal cells,
which attracts HSCs expressing CXCR418 and specic adhesion molecules expressed on bone marrow endothelium.19,20

Submitted September 25, 2014; accepted December 7, 2014. Prepublished

online as Blood First Edition paper, March 11, 2015; DOI 10.1182/blood-201409-570192.

2015 by The American Society of Hematology

BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17

A shelter between blood and bone

Knowledge of the identities and functions of HSC niches has
markedly improved in the past few years (Figure 1). Although the
association of progenitor activity with the endosteum has been
acknowledged for several decades,7 a direct role for osteoblasts in
HSC maintenance has been suggested by experiments showing that
cultured osteoblasts are capable of expanding hematopoietic progenitors in vitro,21,22 which led to studies revealing that the genetic
or pharmacologic manipulation of osteoblast numbers correlates
with HSC counts in the bone marrow.23,24 In addition, imaging of the
transplanted lineage-negative progenitor fraction of bone marrow

2621

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BOULAIS and FRENETTE

BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17

Figure 1. The adult bone marrow HSC niche. The vasculature has emerged as a key structure for the maintenance of HSCs in the bone marrow. Dormant HSCs are found
around arterioles where factors such as CXCL12 and SCF secreted by perivascular, endothelial, Schwann, and sympathetic neuronal cells promote their maintenance. Less
quiescent or activated HSCs are located near sinusoidal niches which are likely diverse in their influence for self-renewal, proliferation, and differentiation. Hematopoietic cells
such as macrophages or megakaryocytes are examples of HSC-derived progeny that can feed back to the niche to influence HSC migration or proliferation. GFAP, glial
fibrillary acidic protein; TGF-b1, transforming growth factor beta-1.

cells shows that progenitors are preferentially distributed along the

endosteal region.25 Osteoblasts have been proposed to support HSC
function by forming direct interactions via N-cadherinmediated
adhesion,24 although this idea has been highly controversial. Functional studies using conditional knockout of N-cadherin (Cdh2) in
hematopoietic and stromal cells,26 osteoprogenitors,27 and osteoblasts28 have not revealed any change in HSC numbers, although
overexpression of N-cadherin has been reported to alter HSC numbers.29
Activated osteoblasts can produce osteopontin, which limits HSC
expansion,30 as well as angiopoietin-1 and thrombopoietin, which
bind the Tie2 and MPL receptors, respectively, and contribute to
HSC quiescence.6,31,32 Bone resorption and the subsequent release
of calcium by osteoclasts also promote HSC maintenance and
localization to the endosteal region.33,34 By contrast, the signaling
lymphocytic activation molecule cell surface markers CD150 and
CD48 have identied HSCs in proximity to sinusoidal blood vessels.35
Using a knockin mouse strain expressing green uorescent protein
(GFP) driven in the Cxcl12 locus, a chemokine critical for the maintenance and quiescence of HSCs, perivascular cells known as
CXCL12-abundant reticular (CAR) cells are reported to contact
HSCs mainly near sinusoids in endosteal and nonendosteal marrow.36
In vivo imaging of the bone marrow in the calvarium reveals that
specic sinusoidal domains expressing both CXCL12 and E-selectin
are targeted for homing and engraftment of normal and leukemic
HSCs.37 Innervation by the sympathetic nervous system regulates
HSC mobilization through circadian release of noradrenaline, which
modulates CXCL12 expression in the bone marrow.38,39 In addition,
sympathetic nerves play a critical role in bone marrow regeneration
in which ablation of adrenergic innervation in the bone marrow

impairs HSC recovery after chemotherapy.40 Physical association

between nerves and bone marrow vasculature also supports the importance of a vascular niche for HSCs. Recent imaging studies of the
bone marrow did not reveal a signicant association between osteoblasts and HSCs.41,42 These data and the selective deletion of critical
niche factors in osteoblasts (see Perivascular niches dictate HSC fate),
argue that osteoblasts do not directly contribute to HSC maintenance.
Although it has been suggested that the endosteal region is
enriched in HSCs, its boundary may not be as narrow as initially
suggested.43 The endosteum is highly vascularized by the presence
of sinusoids with CAR cells36 and also with arterioles that often run
along the endosteal area,42 both of which are associated with HSCs.
After transplantation in irradiated mice, HSCs preferentially home
to the endosteal surfaces of the trabecular bone region but randomly
distribute in nonirradiated recipients.44,45 HSCs undergo expansion
after bone marrow damage in the endosteal region where osteoblasts
and blood vessels are in close proximity.44,45 Lethal irradiation is
known to disrupt the sinusoidal network, which may account for the
relocalization of HSCs to the endosteum.46 Since the endosteum is
vascularized with arteriolar vessels that are more resistant to genotoxic
insults, it is likely that vascular niches differentially contribute to bone
marrow regeneration.

Perivascular niches dictate HSC fate

By tracking the origins of HSCs, studies have linked HSC activity to
vascular development.15 The endothelial layers of the dorsal aorta along

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BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17

with the vitelline and umbilical arteries have been proposed as primary
sites for the emergence of denitive HSCs.11,47 Defective angiogenesis
in AML1-decient mice that lack denitive hematopoiesis can be
rescued by the presence of HSCs, which suggests that they can play role
in shaping the vascular network during development.48 By using
Runx1-lacZ and CD41 markers to mark HSCs, it has been shown that
HSCs are generated in the placental vasculature of mouse embryos
prior to liver colonization.49 Stromal cell lines derived from human
placenta can support the expansion of HSPCs and express pericytic
markers.50 Transcriptome analyses have revealed that organ-specic
molecular signatures are involved in the HSPC supportive activity of
stromal cells.51 The associations among HSCs and perivascular and
endothelial cells suggests that these cell populations can indeed coexist
in an environment that promotes their maintenance and expansion.
Mesenchymal stem and progenitor cell (MSPC) activity was described
decades ago in colony-forming units-broblasts (CFU-Fs),52 but the
lack of unique cell surface markers and the disparity between lineage
tracing models and isolation methods have hampered their characterization. Perivascular human CD1461CD452 MSPCs that reside in the
bone marrow contain virtually all of the CFU-F activity and are capable
of reconstituting a heterotopic bone marrow niche, suggesting that
MSPCs and their progeny contribute to the development of the HSC
niche and regulate hematopoiesis.53 A mouse fetal bone CD511
CD1051CD902CD452Tie22 progenitor cell population is able to
reconstitute the HSC niche by forming donor-derived ectopic bone
through endochondral ossication, thus creating a marrow cavity
with host-derived vasculature and HSCs.54 Other studies have found
that PDGFRa1 Sca-1 1 CD45 2 Ter119 2 (PaS) markers identify
MSPCs capable of differentiating into osteoblasts, reticular cells,
and adipocytes in vivo.55 Transgenic mice that express GFP under the
control of the promoter and second intronic enhancer of nestin
(Nes-GFP),56 an intermediate lament highly expressed in the brain,
allow the prospective identication of perivascular mesenchymal
stem cells that are signicantly associated with HSCs in the bone
marrow. Stem cell activity of these Nes-GFP1 cells is suggested
by the fact that this fraction contains all the CFU-F activity in the
bone marrow and is able to form clonal spheres that can self-renew,
multi-differentiate at the clonal level into the major mesenchymal
lineages, and generate hematopoietic activity in vivo upon serial
transplantation.57 Nes-GFP1 cells express endogenous nestin57,58
and are also closely associated with sympathetic nerves that regulate
the expression of CXCL12 in a circadian fashion.39,57 In further
support of the role of sympathetic nerve bers in regulating the HSC
niche, nonmyelinating Schwann cells that express glial brillary
acidic protein (GFAP) have been reported to activate transforming
growth factor-b1, which promotes HSC quiescence.59 Although
GFAP1 glial cells are described in close proximity to HSCs, only
about a quarter of CD1501CD482CD412Lin2 HSCs appear in direct
contact with them whereas 97% of HSCs were directly associated
with CAR cells,36 and 60% were directly associated with Nes-GFP1
MSPCs.57 However, association of HSCs with these various stromal
cells requires additional statistical analyses to determine the exact
signicance of these relationships. Further renement of cell surface
markers that identify MSPC populations demonstrated that PDGFRa1
CD511CD452Ter1192CD312 stromal cells were enriched for HSC
maintenance genes, formed clonal multipotent self-renewing mesenpheres in culture, and were able to reconstitute a bone marrow niche
heterotopically.58 These PDGFRa1CD511 stromal cells largely
overlap (;75%) with Nes-GFP1 MSPCs and contain the majority
of the CFU-F activity in both adult mice and human fetal bone
marrow.58 They also represent a small subset of CD1461 human
skeletal stem cells enriched in MSPC and HSC niche activities.53

DISSECTING HSC NICHES

2623

Sca-1 is not highly expressed in bone marrow PDGFRa1CD511 cells,

which may suggest that they are stromal cell populations distinct
from the previously identied PaS MSPCs.55 Indeed, the latter were
isolated from crushed bone with discarded bone marrow,55,60
whereas studies with Nes-GFP1 cells have been carried out with
ushed bone marrow. Bones appear to contain a higher concentration of CFU-F (;10-fold greater than bone marrow) and bonederived mesenchymal progenitors expressing Sca-1 whereas the
population of bone marrow mesenchymal progenitors (based on
Nes-GFP) appears mostly negative for Sca-1.58
Endothelial cells that line the sinusoidal blood vessels in the
bone marrow may also contribute to HSC regulation. Disruption of
VEGFR2 and VE-cadherindependent angiogenic signaling pathways that use monoclonal antibodies shows that sinusoidal endothelial cells expand the HSC pool, support self-renewal, and prevent
exhaustion of HSCs in both serum-free coculture assays and in vivo
through Notch signaling.61 Endothelial-specic deletion of Jagged-1
by VE-cadherin-cre reveals that sinusoidal endothelial cells are directly involved in HSC self-renewal for homeostatic and regenerative
hematopoiesis whereas the stromal and perivascular cell compartments,
including PDGFRa1CD511 MSPCs, are not altered in numbers or in
their ability to generate CFU-F cells.62 In contrast, CD31hiendomucinhi
endothelial cells have been proposed to mediate neoangiogenesis in
bone through Notch signaling pathways and to inuence perivascular
osteoprogenitor levels.63,64 Therefore, the activation state of endothelial
cell may play a crucial role in secreting factors that determine the fate of
HSPCs.65 Conditional knockdown of stem cell factor (SCF) in endothelial and perivascular cells by using Tie2-cre and leptin receptor
(LepR)-cre mice, respectively, led to reductions in HSC frequency in
the bone marrow and spleen.66 These functional analyses are consistent
with the expression pattern of GFP knocked into the Scf locus, which
shows that SCF is largely expressed by perivascular cells and mostly
around sinusoids but also near venules and arterioles in the bone
marrow.66 The authors have also suggested that hematopoetic cells
(Vav1-cre), osteoblasts (Col2.3-cre), and nestin1 cells (constitutive
nestin-cre, tamoxifen-inducible nestin-creER) do not represent important contributors of SCF in the bone marrow niche, although the recombination efciency of Scf deletion in nestin1 cells and osteoblasts
was not provided to conrm efcient gene deletion in these cells.66
Recent studies have also determined the contribution of different
niche populations in CXCL12 production.67,68 Targeted Cxcl12 deletion in osteoblasts reveals no HSC or myeloprogenitor phenotypes,
although the authors have noted lower reconstitution of B and T cells
in irradiated mice as well as lower numbers of lymphoid progenitors in the bone marrow using Col2.3-cre mice.68 Conditional deletion
in osteoprogenitors using osterix (Osx)-cre results in hematopoietic progenitor mobilization to the blood and spleen and reduced
B-lymphoid progenitors.67 These results are in accordance with
studies showing that CXCL12 is involved in B-cell maintenance
and that depletion of osteoprogenitors or CAR cells leads to reduction in B-lymphoid progenitor cells.69-71 Endothelial deletion
(Tie2-cre) of CXCL12 reduces HSC frequency, whereas hematopoietic progenitors and lineage reconstitution levels after transplantation are unaffected.67,68 Deletion of CXCL12 in perivascular
stromal cells by using LepR-cre yields no change in HSC number,
progenitor number, or reconstitution level but does show an increase
in mobilization to blood and spleen. Hematopoietic cells (Vav-cre)
and nestin1 MSPCs (Nes-cre) induce no phenotype upon CXCL12
deletion,68 although whether Cre-mediated deletion occurred in
nestin1 cells was not demonstrated, thus limiting any conclusions on
the contribution of Nes-GFP1 cells in CXCL12 secretion. Conversely,
by using transcription factor paired-related homeobox-1 (Prx1-cre),

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BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17

Figure 2. Hierarchy of the stromal niche cells. MSPC populations are found in both bone and bone marrow compartments and contribute to the generation of mesenchymal
lineage cells that generate bone, fat, and cartilage tissues. The relationship between bone-derived MSPCs and marrow MSPCs remains unclear. Stromal cells are also
thought to derive from MSPCs, but the nature or origin of most stromal cells is still obscure. Self-renewing mesenchymal cells and their progeny can be prospectively isolated
by using specific surface markers and lineage tracing approaches with transgenic labeling to decipher the origin of niche cells. Arrows with solid lines indicate that one cell
population that can give rise to another cell population; arrows with dashed lines indicate a relationship between cell populations that remains to be clarified. Mx-1, Myxovirus
resistance-1; Prx-1, paired-related homeobox-1.

which recombines in osteoblasts and bone marrow stromal cells, a clear

reduction in HSC and lymphoid progenitors with an increase in mobilization can be observed.67 Prx1-cre induces recombination in mesenchymal progenitors, which supports the critical role of MSPCs in
forming an HSC niche.
One proposed view of the endosteal niche was that it might provide
a hypoxic environment for maintaining HSCs in a quiescent state
whereas the vascular niche allows HSCs to proliferate and differentiate
in an environment in which oxygen is more available.72,73 Expression
of E-selectin (found exclusively on endothelial cells) promotes HSC
proliferation, whereas E-selectin antagonists promote HSC quiescence
and self-renewal.74 The bone marrow space is uniformly occupied by
sinusoids, but the endosteal region is also highly vascularized and
perfused by arterioles that further subdivide into arterial capillaries
that ultimately connect with sinusoids.75 By using 3-dimensional
bone marrow imaging, it has been determined that Nes-GFP1 cells
with different GFP expression levels discriminate between arterioles
(Nes-GFPbright) and sinusoids (Nes-GFPdim); thus, computational
simulations have determined that quiescent HSCs preferentially
associate with arterioles and that proliferative HSCs move away
from arterioles.42 Nes-GFPbright arterioles are themselves quiescent,
and their integrity is preserved after treatment with 5-uorouracil,
suggesting that they may provide a shelter for quiescent HSCs after
genotoxic insults.42 Furthermore, the pericyte marker NG2 appears
to largely label arteriole-associated Nes-GFP1 cells, whereas LepR
preferentially labels Nes-GFPdimassociated sinusoids.42 Depletion
of NG21 cells also induces HSC cycling and distribution away from

arterioles.42 HSC distribution between proliferative (sinusoids) and

quiescent (arteriole) niches may represent specic milieus that regulate distinct HSC pools.
Consistent with the idea that HSC quiescence is associated with
a hypoxic niche,76,77 quiescent HSCs are enriched in stabilized transcription factor hypoxia-inducible factor-1a (HIF-1a) allowing them
to be maintained and resist stress in hypoxic conditions.78,79 Live in
vivo imaging of oxygen concentration by using phosphorescence
lifetime sensing nanoprobes provides evidence that the most hypoxic
region is located within 40 mm of the bone in the perisinusoidal
region whereas there is a modest increase in oxygen concentration
within 20 mm of the bone in the endosteal region.80 Interestingly,
higher oxygen tension is found around Nes-GFP1 vessels,80 which
harbor quiescent HSCs.42 It is possible that the oxygen tension may
in fact be much lower just outside the relatively thick-walled arterioles. Other studies have revealed that hypoxia, as sensed by
pimonidazole staining, appears HSC autonomous, which raises the
possibility that the hypoxia factors may in fact be regulated through
different cues.41 Indeed, the microenvironment could also inuence
the hypoxic and metabolic prole of HSCs because SCF81 and
thrombopoietin82 are known to increase HIF-1a levels, which could
alter the distribution of hypoxic HSCs. In addition, PaS MSPCs
exhibit a hypoxic prole and are enriched in HIF factors that inhibit
HSPC expansion and differentiation.83 Therefore, studies in the
near future should be able to conrm the existence and the role of
a hypoxic niche and its overlap with quiescent and proliferative
niches.

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BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17

DISSECTING HSC NICHES

2625

Figure 3. Progenitor niches and influence of differentiated progeny. (A) Microenvironment-promoting progenitors. Stromal cells labeled by Prx1-cre or Osx-cre and
expressing CXCL12 (CAR cells) have been shown to regulate both lymphoid progenitor maturation and myeloid progenitor retention. Depletion of CXCL12 in Osxcretargeted stromal cells depletes B-lymphoid progenitor cells and induces the mobilization of myeloid progenitors from the bone marrow. Macrophages also constitute the
central unit of the erythroblastic island allowing erythroblasts to mature and generate red blood cells (RBCs). (B) Regulation by HSC progeny. Macrophages promote HSC
retention in the bone marrow by regulating CXCL12 production from Nes-GFP1 perivascular cells. Macrophage-mediated clearance of neutrophils inhibits the retention
signals, which allows HSC mobilization. Regulatory T cells (Treg) enable an immune privilege site, protecting HSCs against rejection following allogeneic transplantation.
Megakaryocytes localize with HSCs and promote their quiescence. IL-10, interleukin-10.

Hierarchy and crosstalk in the HSC niche

In the adult bone marrow, MSPCs are responsible for the generation
of mesenchymal lineage tissues such as bone, fat, and cartilage as
well as bone marrow stromal cells, which constitute an environment
that supports HSCs and hematopoiesis (Figure 2). Although the
stromal cell composition of the bone marrow is thought to be as
complex as its hematopoietic counterpart, the hierarchical relationship among stromal cells and their inuence on the niche remains
unclear. Myxovirus resistance-1 (Mx-1) induces Cre-mediated recombination in osteogenic progenitors that maintain most of the
osteoblast pool at steady state and after tissue stress, whereas OsxcreERT2 induces only a transient source of osteoblasts in adult
mice.84 Interestingly, when labeling is induced perinatally, longlived bone marrow Nes-GFP1 LepR1 stromal cells capable of
contributing to tissue regeneration after injury are marked by Osx.85
Nes-GFP1 LepR1 stromal cells indeed appear to contain MSPC
activity in the adult bone marrow.85,86 The observation that Osx,
which is a transcription factor thought to be specic for the
osteolineage, marks the stroma during development was independently reported by other groups.87,88 Interestingly, labeling of Osx1
cells during the fetal stage postnatally marked bone marrow stromal
cells, but these cells were short-lived and were replaced by denitive MSPCs during the late fetal and neonatal period.85 These
studies raise the interesting possibility of the presence of a primitive
and denitive bone marrow stroma, both marked by Osx during ontogeny, whose differential characteristics and functions remain to
be dened.
Although much of the focus on bone marrow stroma has been on the
HSC niche, emerging data suggest that subsets of stromal cells also

contribute to the maintenance of hematopoietic progenitor populations (Figure 3A). For example, conditional deletion of CXCL12 in
both osteoblasts and perivascular stromal cells results in a decrease
of common lymphoid progenitors, whereas its deletion in osteoprogenitors is associated with a decrease in committed B-lymphoid
progenitors.67,68 This is consistent with studies showing that depletion
of CAR cells, known to be closely associated with pre-pro B cells,69
reduces both common lymphoid progenitors and pro-B cell levels.70
It is thus possible that the endosteal region might represent a suitable
microenvironment for the maintenance of lymphoid progenitors. In
addition, macrophages constitute the central unit in erythroblastic
islands thereby providing a niche for the maturation of erythropoietic
cells in the steady state, after hemolytic or myeloablative stress, and
during malignant hematopoiesis.89,90
The progeny of HSPCs supplies our body with mature blood cells
which may also constitute important feedback regulators of the HSC
niche (Figure 3B). CD1691 macrophages promote HSC retention by
regulating CXCL12 production in the bone marrow and by inducing
downregulation of HSC maintenance genes in Nes-GFP1 MSPCs.91
Treatment with granulocyte colony-stimulating factor leads to a loss
of monocyte and macrophage populations and functions, which is
associated with HSC egress to the blood.92,93 Regulatory T cells may
also provide an immune privilege site that protects allogeneic HSCs
in the niche after transplantation.94 Neutrophil depletion reportedly
increased CAR cell population and CXCL12 levels in the bone
marrow whereas their clearance by macrophages promoted HSPC
mobilization.95 In addition, recent studies showed that megakaryocytes localize specically with a subset of HSCs, and promotes their
quiescence through the production of CXCL4 (also known as platelet
factor-4)96 and transforming growth factor-b1.97 FGF1 production
by megakaryocytes can also promote HSC expansion under stress.97

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BOULAIS and FRENETTE

Table 1. The HSC niche in acute and chronic myeloid neoplasms

Model
MLL-AF9
AML

MSPC

Osteoblasts

Osteoclasts
(TRAP1)

Adipocytes

Endothelial cells

SNS fibers

Hematopoietic
cells

Reference

Nes-GFP1 cells

Perilipin1

(CD311Ter119CD45)

Th1 fibers

NA

101

CCL3

100

TPO

99

PDGFRa1CD511 cells

cells

Osteoprecursors
(CD511Sca1)
NG21 pericytes
Niche factors
BCR-ABL
blast crisis

CCL3

NA

NA

NA

NA

(LinCD45CD311Sca-11)

NA

CFU-OB

CML
BCR-ABL
CML

CFU-F size
Osteoprecursors

CCL3

(CD511Sca11)
Niche factors
JAK2V617F
MPN

Nes-GFP1 cells

NA

NA

NA

NA

Th1 Fibers

IL-1R

IL-1b

102

GFAP1

Niche factors

Schwann cells

CFU-OB; colony-forming unit-osteoblasts; GFAP, glial fibrillary acidic protein; IL-1R, interleukin 1 receptor; MPN, myeloproliferative neoplasm; NA, not available; SNS,
sympathetic nervous system; TRAP, tartrate-resistant acid phosphatase; Th, tyrosine hydroxylase; TPO, thrombopoietin.

Heterogeneity among HSCs suggests that specic molecular cues

inside the niche will instruct HSC fate at different levels depending on
the targeted subpopulation.98

Niche of hematopoietic malignancies

The importance of identifying and characterizing specic cell populations in the hematopoietic and stromal hierarchy is underscored
by their involvement in myeloid neoplasms (Table 1). Interestingly,
alteration of the microenvironment by the deciency in retinoic acid
receptor, for example, appears sufcient to induce a myeloproliferative syndrome.103 Simultaneous deletion of retinoblastoma protein
in myeloid cells and the stromal compartment can also enhance
myeloproliferative diseases.104 In addition, the deletion of Dicer1
in osteoprogenitors (using Osx-cre) but not mature osteoblasts
(osteocalcin-cre) promotes myelodysplastic syndrome and acute
myeloid leukemia (AML), indicating that alterations in specic
stromal cell populations can induce a hematopoietic malignancy.105
Overexpression of b-catenin in osteoblasts (driven by Col1-cre) can
also induce myelodysplastic syndrome /AML via increased Jagged-1
expression and Notch signaling.106 Treatment with an inhibitor
of gut serotonin restores osteoblast number in leukemic mice and
suppresses acute lymphoblastic leukemia and AML progression.107
Because osteoblasts have a high turnover, it is likely that alterations
at the MSPC level rather than the osteoblast are driving nicheinduced hematopoietic malignancies. The expression of Osx-cre
in MSPCs85 and the continuous overexpression of b-catenin in
osteoblasts106a situation unlikely to occur naturallyare also
consistent with this idea, although this has not been formally
demonstrated. Distinct signals in the microenvironment may also
differentially alter malignant transformation, as suggested by the
expression of a constitutively active PTH receptor in osteoblasts that
inhibits chronic myelogenous leukemia (CML)-like myeloproliferation while enhancing MLL-AF9driven AML.108 MSPC differentiation toward the osteoblastic lineage in BCR-ABL CML results in
increased mature osteoblast numbers99 in contrast to BCR-ABL
CML blast crisis.100 Similar expansion of MSPCs has recently been

reported for AML, which destroys sympathetic nerves in bone

marrow and spleen that are inltrated with AML. The loss of
adrenergic activity in the bone marrow environment leads to the
proliferation of nestin1 cells primed to differentiate into the osteoblastic
lineage. Blockade of the b2-adrenergic receptor enhanced AML inltration whereas a b2-adrenergic agonist reduces disease activity.101
Interestingly, a similar effect of JAK2V617F-driven myeloproliferative
syndrome is observed on bone marrow innervation but the disease,
by contrast, leads to the depletion of nestin1 cells, and this could be
rescued by b3-adrenergic agonists.102 Further analyses are needed to
dissect the inuence of cancer on the bone marrow microenvironment to nd the common abnormalities and the cancer type-specic
abnormalities.

Concluding remarks
Many, but not all, discrepancies in the literature regarding the osteoblastic vs the vascular niche can be explained by unfaithful mapping
of the fate of osteoblast promoters that are in fact expressed throughout the mesenchymal lineage. Uneven recombination efciencies of Cre
recombinase among cell types and transgenic mouse strains also represent meaningful sources of variability and a substrate for controversy.
Further understanding the complexity of the HSC niche will be
achieved by targeting specic niche cells to shed light on contributions of overlapping cell populations. Recent studies have established
a major role for the vasculature in HSC maintenance, and subsets
of microenvironments have emerged from these studies. Feedback
mechanisms and crosstalk by mature hematopoietic cells have also
been established. Although the interplay between the hematopoietic
and nonhematopoietic compartments is likely more complex than we
imagine, common principles will guide the design of new approaches
to tackle hematologic diseases. Hematologic malignancies represent
an area that will likely benet from niche-targeted therapies against
cancer-mediated attacks on the healthy microenvironment. For example, therapies that preserve innervation, differentiation, or loss of
healthy niche cells in myeloid neoplasms may maintain normal HSC
function while preventing the establishment of a cancer-promoting

From www.bloodjournal.org by guest on June 16, 2015. For personal use only.
BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17

DISSECTING HSC NICHES

niche. New insights from HSC niches in the extremes of life (development and aging) will allow the identication of new cellular and
molecular players involved in the regulation of hematopoiesis. This
knowledge will one day be exploited to engineer ex vivo niches for
HSC expansion and to allow the discovery of novel pharmacologic
approaches for blood diseases.

2627

R01 grants DK056638 from the National Institute of Diabetes and

Digestive and Kidney Diseases and HL069438 from the National,
Heart, Lung and Blood Institute (P.S.F.).

Authorship
Acknowledgments
The authors apologize to those whose work was not cited because of
space limitations.
This work was supported by the New York State Department of
Health (NYSTEM Program) and by the National Institutes of Health

Contribution: P.E.B. and P.S.F. wrote and revised the manuscript.

Conict-of-interest disclosure: The authors declare no competing
nancial interests.
Correspondence: Paul S. Frenette, Ruth L. and David S. Gottesman
Institute for Stem Cell and Regenerative Medicine, Albert Einstein
College of Medicine, Price Center, Room 101B, 1301 Morris Park Ave,
Bronx, NY 10461; e-mail: paul.frenette@einstein.yu.edu.

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2015 125: 2621-2629

doi:10.1182/blood-2014-09-570192 originally published
online March 11, 2015

Making sense of hematopoietic stem cell niches

Philip E. Boulais and Paul S. Frenette

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