Influences of vascular niches on hematopoietic stem cell fate
Yuya Kunisaki
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Paul S. Frenette
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Y. Kunisaki P. S. Frenette Department of Medicine, Albert Einstein College of Medicine
, Bronx,
NY 10461, USA
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Y. Kunisaki P. S. Frenette Department of Cell Biology, Albert Einstein College of Medicine
, Bronx,
NY 10461, USA
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Y. Kunisaki P. S. Frenette (&) Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
, Bronx,
NY 10461, USA
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Present Address: Y. Kunisaki (&) Department of Medicine and Biosystemic Science, Kyushu University
, Fukuoka, Fukuoka 812-8582,
Japan
The fate decision of hematopoietic stem cells (HSCs), quiescence, proliferation or differentiation, is uniquely determined by functionally specialized microenvironments defined as the HSC niches. However, whether quiescence and proliferation of HSCs are regulated by spatially distinct niches is unclear. Although various candidate stromal cells have been identified as potential niche cells, the spatial localization of quiescent HSCs in the bone marrow remains controversial. In our recent study, we have established whole-mount confocal immunofluorescence techniques, which allow us to precisely assess the localization of HSCs and their relationships with stromal structures. Furthermore, we have assessed the significance of these associations using a computational simulation. These novel analyses have revealed that quiescent HSCs are specifically associated with small caliber arterioles, which are predominantly distributed in the endosteal bone marrow while the associations with sinusoidal vessels or osteoblasts are not significant. Physical ablation of the
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arteriolar niche causes the shift of HSC localization to
sinusoidal niches, where HSCs are switched into
non-quiescent status. This new imaging analyses together with
previous studies suggest the presence of spatially distinct
vascular niches for quiescent and non-quiescent
(proliferating) HSCs in the bone marrow.
Hematopoietic stem cells Quiescence
Hematopoietic stem cells (HSCs) maintain hematopoietic
homeostasis through lifelong replenishment of all blood
cell lineages by a finely tuned orchestration of self-renewal
and differentiation controlled by specific cellular and
molecular microenvironments defined as niches [1]. The
niche concept has been validated by numerous studies
since Schofield postulated its presence in 1978 [2]. Most of
HSCs divide infrequently and are quiescent in the niche
[3]. However, they are reversibly activated in response to
hematopoietic stresses [4]. Cell cycle quiescence is a key
behavior of stem cells, which protects them from being
exhausted by exogenous insults [5] and is also assumed to
prevent them from acquiring genetic mutations that
potentially result in consequent malignant transformations
[6]. Although quiescence and proliferation of HSCs are
thought to be regulated by their microenvironments, it
remains unclear whether and if so how spatially distinct
niches control cell cycle status.
The identification of cellular constituents of the HSC
niche has recently been the subject of intense
investigations. Osteoblasts have been proposed to promote HSC
quiescence via direct contact [7] and the secretion of
angiopoietin-1 [8] or osteopontin [9, 10]. On the other
hand, an emerging role of the bone marrow vasculature has
recently gained support and interest [11] as other studies
have found that most HSCs are localized adjacent to blood
vessels (sinusoids), near perivascular cell populations
characterized as CXCL12-abundant reticular (CAR) cells
[12, 13], Nestin? mesenchymal stem cells [14], and Leptin
receptor (LEPR)? cells [15]. Based on the previous studies,
a prevalent unifying interpretation of the literature has been
that the osteoblastic and vascular niches could confer
distinct microenvironments promoting HSC quiescence and
proliferation, respectively. However, this popular concept
has not been supported by rigorous analyses. Recent
studies further have reported that endothelial cells and
perivascular stromal cells are sources of the factors such as
CXCL12 and stem cell factor (SCF), known to be essential
for HSC retention and maintenance [1416]. Series of
studies also have shown that genetic deletion of the factor,
CXCL12, in osteoblasts [17] and ablation of osteoblasts
(David T. Scadden personal communication) affect
lymphoid-committed progenitors rather than HSCs. On the
other hand, the proximity of HSCs to sinusoidal vessels,
which has been reported in many previous studies, might
be biased by the abundance and dense network of sinusoids
in the bone marrow. The relationship between HSCs and
arteries has been well documented in the emergence of
HSCs during development as definitive hematopoiesis is
beginning in the aortagonadmesonephros (AGM) region
[18]. However, it has been unknown whether arteries play
specific roles for HSCs in adult bone marrow.
To address these issues, we have established a
wholemount immunofluorescence imaging technique in which
the thre (...truncated)