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Blood First Edition Paper, prepublished online July 11, 2012; DOI 10.1182/blood-2012-04-424507
PERSPECTIVES
Two anatomically distinct niches regulate stem cell activity
Running title: Stem cell niches
Hideo Ema and Toshio Suda
Department of Cell Differentiation, Sakaguchi Laboratory of Developmental Biology,
Keio University School of Medicine
35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
Tel & Fax: (81)-3-5363-3474
E-mail: [email protected]
Keywords:
stem cells, niche, hematopoietic stem cells, intestinal stem cells,
interfollicular epidermal stem cells, hair follicle stem cells, Paneth cells, bulge
1
Copyright © 2012 American Society of Hematology
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Summary
The niche microenvironment controls stem cell number, fate, and behavior. The bone
marrow, intestine, and skin are organs with highly regenerative potential, and all
produce a large number of mature cells daily.
Here, focusing on adult stem cells in
these organs, we compare the structures and cellular components of their niches and the
factors they produce. We then define the niche as a functional unit for stem cell
regulation. For example, the niche possibly maintains quiescence and regulates fate in
stem cells. Moreover, we discuss our hypothesis that many stem cell types are regulated
by both specialized and non-specialized niches, although hematopoietic stem cells, as an
exception, are regulated by a non-specialized niche only. The specialized niche is
composed of one or a few types of cells lying on the basement membrane in the
epithelium. The non-specialized niche is composed of various types of cells widely
distributed in mesechymal tissues. We propose that the specialized niche plays a role in
local regulation of stem cells, while the non-specialized niche plays a role in relatively
broad regional or systemic regulation. Further work will verify this dual-niche model to
understand mechanisms underlying stem cell regulation.
2
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Introduction
Stem cells are defined by self-renewal and differentiation potential. Tissue-specific stem
cells play an essential role in tissue generation, maintenance, and repair. A large
number of blood cells, epithelial cells, and epidermal cells are produced daily over an
individual’s lifetime. To understand how stem cells that give rise to these tissues are
regulated extrinsically and intrinsically is a fundamental issue in biology and also
highly relevant to regenerative medicine.
Stem cells reside in a microenvironment known as the niche. Schofield, who was the
first to put forth the concept of stem cell niche, proposed that the niche (1) provides an
anatomical space to regulate stem cell number; (2) instructs a stem cell to either
self-renew in close proximity or commit to differentiation at a distance; and (3)
influences stem cell motility 1. Lajtha first proposed that most stem cells are not cycling,
that is, are in G0 phase 2. To be able to return to a quiescent state from cycling is perhaps
one of the most important properties of a stem cell because progenitor cells cannot do
so.
The importance of the niche has not been fully appreciated in part because
stochastic rather than instructive models of stem cell behavior have been preferred 3.
The stochastic model predicts that stem cell fate is determined randomly. Thus far it has
been difficult to show that the likelihood of self-renewal is influenced by external
3
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factors. To understand niche function may require application of an instructive model.
Analysis of germline stem cells (GSCs) in the fruitfly Drosophila melanogaster
suggests that niche factors govern asymmetric division 4. In the ovary, two or three
GSCs reside in a niche composed of cap cells and other cells. When a GSC gives rise to
two daughter cells, one remains a stem cell in the niche upon receipt of a
decapentaplegic (Dpp, a homolog of human bone morphogenetic proteins 2 and 4)
signal. The other moves out of the niche and begins the differentiation program 4. This
asymmetric division would have been exactly what Schofield would have predicted.
This early work in Drosophila led to an interest in the niche regulation of adult stem
cells in mammals.
Here we summarize progress in understanding of the stem cell niche since
publication of an excellent review by Moore and Lemischka 5. Hematopoietic stem cells
(HSCs) are the best studied, as transplantation assays were established for this cell type
early on and their purification techniques have progressed significantly
6,7
. The niche
concept also emerged from studies of HSCs. Intestinal stem cells (ISCs) provide a
simpler stem cell system that produces epithelial cells continuously 8. In that system, not
only do stem cells and niche cells lie next each other, but stem cells may create their
own niche 9. Hair follicular stem cells (HFSCs) have been successfully marked with
4
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β-gal or fluorescent proteins, enabling in vivo tracing studies. Clonal assays are crucial
to analyze stem cell differentiation potential, and it is now possible to study single
HSCs, ISCs, and HFSCs
10-14
. We focus on the niche of these three types of adult stem
cells because they share certain properties. We examine stem cell heterogeneity, niche
components, and extrinsic niche signals regulating stem cells, and discuss the niche as a
functional unit. Lastly, we introduce of the concept that specialized and non-specialized
niches regulate stem cell activity.
5
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The hematopoietic stem cell niche
Functional heterogeneity of HSCs has been suggested
self-renewal potential.
15
, particularly with regard to
CD34-negative, Kit-positive, Sca-1-positive, and lineage
marker-negative bone marrow cells are highly enriched in mouse adult bone marrow
HSCs
10
.
Among this population, HSCs with high self-renewal potential express
CD150 at higher levels than do HSCs with limited self-renewal potential
16-18
.
Self-renewal potential may also be inversely proportional to the number of divisions a
cell has undergone19. Only when sensitive methods to monitor the division history of
cells become available will the molecular basis for HSC self-renewal potential in HSCs
be thoroughly understood.
Most HSCs presumably enter the cell cycle once a month
so-called “dormant” HSCs entering the cycle less frequently
may be interchangeable
20-22
23
, with the remaining
. These two cell types
24
. Of note, both types are in G0 phase. Single-cell
transplantation studies have revealed a rare HSC subset, latent HSCs, that show
significant repopulating activity only after secondary transplantation, suggesting latent
HSCs have long quiescent intervals
influenced by different niches.
18
. Alternatively, quiescent intervals of HSCs are
In support of this concept, it has been found that bone
marrow and spleen HSCs are functionally equivalent but their quiescence times differ 25.
An interpretation of these data would be that quiescent intervals are cell-extrinsically
6
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regulated in most HSCs but are cell-intrinsically determined in a particular type of
HSCs.
Angiopoietin-1 (Ang-1) and transforming growth factor (TGF) β1 maintain HSCs in
G0 phase 26,27. HSCs express the receptor tyrosine kinase Tie2, and its ligand Ang-1
inhibits HSC division in vitro. Ang-1, expressed in osteoblasts and mesenchymal cells,
likely supports HSC quiescence in vivo through integrins and N-cadherin26. TGFβ1,
which is produced by several different types of cells, must be activated from a latent
form.
Elegant studies indicate that integrin αvβ8-mediated TGFβ activation is
essential to induce regulatory T cell activation and prevent autoimmune disease
28
.
Moreover, structural analysis suggests that specific integrins are required to generate an
active form of TGFβ1 from the latent form 29.
These data indicate that cells expressing
integrin β8 may play a role similar to TGFβ1 activation in bone marrow. For example,
Schwann cells appear to be such integrin β8+ cells, suggesting that they participate in
niche function 30.
Adult HSCs, and likely their niches, are widely distributed in marrow of various bones
in the body rather than in any particular anatomical site. Moreover, HSCs are not
necessarily locked in the niche but instead are mobile
31
. Nevertheless, investigators
currently propose both endosteal and perivascular HSC niches (Fig. 1). The endosteal
7
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niche is mainly composed of osteoblasts
vascular endothelial cells
reticular (CAR) cells
35
32,33
. The perivascular niche is composed of
16
, mesenchymal stem cells (MSCs)
, perivascular stromal cells
Macrophages may also participate in the niche
37,38
.
36
34
, Cxcl12-abundant
, and Schwann cells
30
.
After highly purified HSCs were
transplanted into irradiated mice, homing analysis detected transplanted HSCs near the
endosteum, particularly in the trabecular area 39,40.
Since that area is well-vascularized,
it is likely the primary homing site. These data suggest that both endosteal and
perivascular niches are present in the trabecular area. Whether the endosteal niche
regulates HSCs differently than the perivascular niche does is not clear. One attractive
hypothesis is, however, that infrequently cycling HSCs reside in the endosteal niche,
while frequency cycling HSCs reside in the perivascular niche 23,41. It will be necessary
to demonstrate that HSCs migrate from the endosteal zone to the perivascular zone, or
the other way around, to verify the two-zone model for stem cell regulation 41.
Stem cell factor (SCF; c-Kit ligand)
candidate niche factors.
36
, thrombopoietin
42,43
, and Cxc112
35
are
SCF expression is detected in blood cells, osteoblasts, nestin+
mesenchymal cells, endothelial cells, and perivascular stromal cells
36
. Conditional
deletion of SCF in endothelial cells and perivascular stromal cells, but not in blood cells,
osteoblasts, or nestin+ mesenchymal cells, results in a significant decrease in HSC
8
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number, suggesting that endothelial cells and perivascular stromal cells play a major
role in HSC maintenance 36.
SCF, Cxcl12, Pdgfr, and the leptin receptor are apparently
similarly expressed in both perivascular stromal and CAR cells; thus these cells likely
overlap. Interestingly, pericytes may be closely related to MSCs
44
, suggesting that
MSCs are a heterogeneous population, a portion of which overlaps with perivascular
stromal and CAR cells.
The intestinal stem cell niche
The ISC niche is less complex (than the HSC niche): the epithelial monolayer is
composed of one type of absorptive cell (enterocyte) and four types of secretory cells
(Goblet, Paneth, enteroendocrine, and Tuft cells) 45. The mucosal surface forms crypts
which project downward and villi which project upward.
Stem cells have been
identified in the crypt of the small intestine, which consists of the duodenum, jejunum
and ileum. Two types of ISCs, leucine-rich G protein-coupled receptor 5 (Lgr5)+ stem
cells and Bmi1+ stem cells, have been characterized (Fig. 2).
Lgr5+ stem cells (also
called columnar basal cells) reside at the crypt base (10 or more per crypt) and
continuously cycle
46,47
. Paneth cells, which are distributed between stem cells at the
base of the crypt, secrete lysozyme and antimicrobial peptides such as defensins to
9
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protect epithelial cells from infection and are now considered to be niche cells 9. Lgr5+
stem cells give rise to both themselves and Paneth cells, which in turn regulate stem
cells 9.
It is suggested that infrequently cycling stem cells are located around the +4
position in the crypt (the fourth cell above the base) 8 although positions can range from
+2 to +7. These stem cells express the polycomb group protein Bmi1
48
. Whether
Bmi1+ stem cells express Lgr5 or Lgr5+ stem cells express Bmi1 is not yet clear.
The diphtheria toxin (DT) receptor (DTR) is expressed in human but not mouse cells
49
. The DTR gene has been knocked into the mouse Lgr5 locus in order to kill Lgr5+
stem cells conditionally with DT 50.
After Lgr5+ stem cells but not Bmi1+ stem cells
were eliminated, the crypt was maintained. Furthermore, lineage tracing shows that
Bmi1+ stem cells give rise to Lgr5+ stem cells, suggesting a hierarchical organization
among these two stem cell populations.
R-spondin1 (Rspo1), which activates the canonical Wnt pathway, reportedly induces
epithelial hyperplasia in the intestine after injection into normal mice
51
. It was found
that Rspo1 along with Noggin and epidermal growth factor can form crypt-villus
structures from single Lgr5+ stem cells in culture (organoid culture) 12. The Lgr family
(Lgr 4, 5, and 6) proteins are 7-transmembrane receptors, as are Frizzled proteins.
Frizzled forms a heterodimer receptor for Wnt, with LDL receptor-related protein (Lrp)
10
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5/6. Lgr had long been an orphan receptor, but Lgr appears to form a heterodimer
receptor for Rspo, with the Lrp 5/6
synergistically to activate β-catenin
52-54
52-54
.
Interestingly, Wnt3a and Rspo1 act
. If these ligands share a common signal
transducer, it is not yet clear how this synergy can be explained, although it is also
possible that different signaling pathways are activated by Wnt3a and Rspo1.
Paneth cells reportedly express Wnt3, Wnt11, Rspo1, epidermal growth factor (EGF),
transforming growth factor (TGF) α, and Dll4
9,55
, and these factors likely regulate
Lgr5+ stem cell cycling. Nonetheless, how Bmi1+ and Lgr5+ stem cells are differently
regulated under similar circumstances remains unknown. Paneth cells also require
further study to define their niche function and identify their niche factors.
The hair follicle stem cell niche
The skin is composed of the epidermis, dermis, and hypodermis (subcutaneous fatty
layer). The epidermis is of ectodermal origin, while the dermis and hypodermis are
mesoderm-derived. The epidermis is composed of a multi-layered epithelium. Skin cells
exhibiting hairs have an appendage called the pilosebaceous unit consisting of the hair
shaft, hair follicle, sebaceous gland, and erector pili muscle (Fig. 3).
membrane separates the epidermis from the dermis.
The basement
Skin stem cells are located in two
11
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distinct regions: interfollicular epidermal stem cells (IFESCs) are found in the basal
layer of the epidermis and hair follicle stem cells (HFSCs) reside at the bottom of the
non-cycling portion in the outer root sheath, in a region called the bulge.
IFESCs play a major role in adult epidermal homeostasis. When they exit the cell
cycle and commit to differentiation, they give rise to keratinocytes. Despite their
essential role, IFESCs have not yet been isolated. Whether all or just a portion of cells
in the basal layer constitute the stem cell pool is unclear. Studies of the skin, particularly
in the mouse tail, suggest that a single population of proliferating progenitors is
sufficient for homeostasis of epidermis
56
. This finding challenges the fundamental
concept of stem cells because highly proliferative tissue like the epidermis can be
maintained without stem cells. Nevertheless, little is yet known about the IFESC niche.
Under physiological conditions, HFSCs mainly regenerate the hair follicle, which
cycles through anagen (growth), catagen (apoptosis), and telogen (quiescence) phases.
Keratin (K) promoter-driven reporters were first used to mark bulge stem cells
57,58
.
The K5 promoter-driven tetracycline-off system was used for conditional labeling of
K5-expressing cells with histone H2B-GFP fusion protein in the bulge
57
. The K15
promoter-derived fusion protein consisting of Cre recombinase and a truncated
progesterone receptor was also used for conditional labeling of K15-expressing cells in
12
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the bulge 58. These K15-Cre mice were crossed with Cre-responsive R26R reporter mice
58
. In this system, Cre is translocated to the nucleus only in the presence of the
progesterone agonist. Infrequently cycling cells were detected and isolated using these
markers and characterized, suggesting the presence of K5+ stem cells and K15+ stem
cells in the bulge. Since then, various promoters have been used to mark HFSCs
59
.
Lgr5+ stem cells have also been found near the bulge 60 and can give rise to follicle cells,
sebaceous cells, and interfollicular epidermis but mainly contribute to the hair follicle
under physiological circumstances. Sox9 and Gli1 seem to be also expressed in these
stem cells 61,62.
The upper portion of the bulge apparently contains stem cells different from those in
the middle and lower portions (Fig. 3).
Lgr6+ cells found in the upper portion mainly
give rise to sebaceous gland cells and interfollicular epidermis 63.
In addition, Lring1+
cells and Mts24+ cells are found in the isthmus, the junction between the epidermis and
the hair follicle (Fig. 3)
64,65
. These stem cells mainly give rise to interfollicular
epidermis. Blimp1+ cells found in sebaceous glands only give rise to sebaceous gland
cells 66. These cells may be progenitors rather than sebaceous gland-restricted stem cells.
Various overlapping populations of stem cells or progenitors are seen in, near, and
13
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moving around the bulge
67
.
It is not known whether there is a hierarchical order in
these populations, and whether specific niches control different stem cells.
Growth of the hair germ (Fig. 3) is stimulated by sonic hedgehog signaling from the
dermal papilla 68, which behaves like a niche for these cells. HFSCs are in close contract
with the dermal papilla at the telogen. Thus, the dermal papilla can also temporarily act
as a stem cell niche. IFESCs and HFSCs are also regulated by signaling from the dermis
69
. Periodic Wnt/β-catenin signaling positively regulates the hair follicle cycle, and
periodic secretion of bone morphogenetic proteins (Bmp) 2 and 4 negatively regulates
the hair follicle cycle
69
. Bmp2 is produced by adipocytes, and Bmp4 is produced by
dermal papilla, dermal fibroblasts, and interfollicular epithelium. Although the bulge
has been implicated as the HFSC niche, little is known of its cellular components and
factors.
The niche as a functional unit
Currently, proposed niche functions include regulation of stem cell number, cell cycle,
fate determination, and motility. For example, stem cell number is thought to be
maintained constant by the niche under physiological conditions. To date, however, we
have no evidence for that the physical space in the mammalian niche determines the
14
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number of stem cells as originally proposed by Schofield 1. We rather think that stem
cell number is regulated in a more complex manner (Fig. 4). The niche likely provides
positive and negative factors controlling proliferation. In addition, positive and negative
feedback from progenitors likely maintains stem cell supply and demand, as are
autocrine and paracrine mechanisms. Feedback signaling may also be mediated by the
niche. The probability that a stem cell makes a decision to self-renew should be taken to
account as well.
These regulations have long been postulated but so far no study has
successfully shown the existence of such a regulatory system. Perhaps, we are only able
to address this issue by using mathematical modeling and computational analysis.
The maintenance of stem cell quiescence is a common niche feature. Both cycling
and non-cycling stem cells have been found in the small intestine and skin 46 48 56. Stem
cells are distinguished from progenitors in the hematopoietic system, providing the
principle for hierarchical organization. Once again, most HSCs are in G0 phase, whereas
most hematopoietic progenitors are cycling. Although it is yet to be demonstrated, some
cycling stem cells in the intestine and skin may act as progenitors.
Among the TGFβ superfamily, BMP2 and BMP4 negatively regulate the cell cycle in
HFSCs and ISCs
69,70
, and TGFβ1 negatively regulates the cell cycle in HSCs
27,30
.
Smad1, 5, and 8 mediate BMP signaling, and Smad 1 and 5, but not Smad8, are
15
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expressed in HSCs. Conditional Smad1 and 5 double knockout mice exhibit normal
HSC function, but show intestinal abnormalities 71. TGFβs but not BMPs are negative
regulators for HSCs. Quiescence of ISCs, HFSCs, and HSCs may be similarly regulated
by TGFβ superfamily members.
Wnt and Notch signaling plays crucial roles in cell fate determination in embryonic
development and are therefore candidate niche factors. In the absence of Wnt protein,
β-catenin is sequestered in the cytoplasm by a large complex consisting of APC, axin,
casein kinase 1α, and glycogen synthase kinase 3β (GSK3β).
complex is phosphorylated, ubiquitinylated, and degraded.
β-catenin in that
In the presence of Wnt
signals, axin is recruited to the Frizzled/Lrp5/6 receptor, and β-catenin is free to move
into the nucleus to interact with a member of the Tcf/Lef family to activate transcription
of target genes 72.
Activating point mutations of β-catenin are seen in colorectal cancer
pilometrixoma, a benign skin tumor
74
73
, and in
. They are not, however, seen in leukemia
75
.
Analyses of conditional β-catenin knockout mice show that β-catenin is essential to
maintain ISCs
76
and HFSCs
77
. The role of Wnt/β-catenin signaling in regulating
HSCs, however, remains controversial 78-82.
Notch receptors (Notch1, 2, 3, 4) and their ligands (Delta1, 3, and 4, and Jag1 and 2)
16
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exist as transmembrane proteins. So called canonical Notch signal pathway is
summarized as follows: ligand binding stimulates two sequential proteolytic cleavages
of Notch receptor, mediated by a tumor necrosis factor α-converting enzyme and a
presenilin-dependent γ-secretase
83
. The Notch intracellular domain (NICD) then
translocates to the nucleus where it interacts with a complex consisting of
recombination signal binding protein for immunoglobulin kappa J region (Rbpj-κ) and
Longevity-assurance gene-1. Basic helix-loop-helix transcription factors in the Hes and
Hey families are upregulated by signaling 83.
NICD transgenic mice in which NICD was expressed in all intestinal epithelium
using the Villin promoter, showed hyperplasia of the intestinal epithelium with a
complete loss of goblet cells
84
. In contrast, conditional Rbpj-κ knockout mice
constructed using P450-Cre, exhibit increased numbers of goblet cells in the intestinal
epithelium and decreased enterocytes
85
. These data indicate that Notch signaling is
required for ISCs to commit to an enterocyte rather than a goblet cell lineage.
Interestingly, treatment of APC mutation-induced adenoma cells with a γ-secretase
inhibitor converted them to goblet cells, suggesting cross-talk between Notch and Wnt
signaling pathways 85.
NICD transgenic mice in which NICD was expressed in the skin using the Involucrin
17
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promoter showed enhanced differentiation of epidermal keratinocytes
86
. In contrast,
conditional Rbpj-κ knockout mice harboring K14-Cre, showed thinner epidermis
87
,
suggesting that Notch signaling promotes IFSC differentiation into keratinocytes.
Notch-dependent asymmetric division is suggested to be required for IFSC
differentiation 88. It has also been reported that Notch signaling acts downstream of Wnt
signaling to determine epidermal cell fate 89.
Notch1 is activated under control of the T cell receptor-β locus in human T cell acute
lymphoblastic leukemia via the t(7;9) chromosomal translocation 83. Notch1 is essential
for generation of HSCs in the aorta-gonad-mesonephros region
90
and for T cell
commitment in the thymus 91. T cell leukemia can be induced in mice transplanted with
NICD-transduced bone marrow cells
92
. Conditional Notch1/2 double knockout mice
harboring Mx1-Cre develop chronic myelomonocytic leukemia
93
. These data indicate
that Notch signaling can either positively or negatively regulate commitment or
proliferation, depending on blood lineage. In this regard, Notch signaling may be more
important at the progenitor level than at the stem cell level.
HSCs enter the circulation at a low but constant rate
31
.
Intra- and inter-marrow
mobilization of HSCs may occur in physiological conditions.
This issue has not been
directly addressed, because, unlike HFSCs and ISCs, HSCs have not been specifically
18
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marked using fluorescent reporters. HFSCs appear to move back and forth between
the bulge and the hair germ regions 67, and ISCs may similarly move around the crypt
base. The question remains, do HFSCs move into different follicles and do ISCs move
into different crypts? Single stem cell-derived progeny apparently occupy one crypt, but
likely not two or more 94. Classically, the niche is physically close to or in direct contact
with stem cells so that membrane-bound proteins can serve as niche signals; soluble
factors can also regulate stem cells, and extracellular matrix (ECM) provides structural
support and functions in adhesion and provides a spatial context for signaling
95
.
If
HFSCs and ISCs are regulated only by neighboring niches, are the large numbers of
stem cells distributed in the body regulated totally independently?
One possibility is
that there could be another type of niche covering wider areas: for instance, the dermis
for HFSCs and IFESCs or the lamina propria for ISCs.
Specialized and non-specialized niches
We propose two types of niches, based on the anatomical structure, and hypothesize
that each plays a distinct role in stem cell regulation. One can be viewed as a specialized
niche, while the other is non-specialized (Fig. 5). Most stem cells are presumably under
the dual regulation of both niche types. The specialized niche, composed of one or a few
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cell types, resides next to stem cells to support them directly (local regulation). Both
stem cells and specialized niche cells together rest on a basement membrane of
specialized ECM consisting of laminins, collagen IV, perlecan, and nodogens 96.
The
basement membrane is considered a portion of the specialized niche that directly
regulates the cell cycle and stem cell polarity.
The specialized niche could also be
termed the epithelial niche because specialized niche cells are often present in the
epithelium.
The non-specialized niche is composed of mesenchymal cells such as mesenchymal
stem cells, fibrocytes, fibroblasts, adipocytes, vascular endothelial cells, neurons, and
blood cells. Signals from the non-specialized niche are likely not as simple as those
from the specialized niche because they are multiple and impact stem cells directly and
indirectly. The non-specialized niche may also affect stem cells via a specialized niche
or be responsible for spatial organization or regional synchronization of stem cells.
If
stem cells are damaged in a particular region, the remaining stem cells could be
recruited to that region to rescue them. In this sense, the non-specialized niche plays a
role in relatively broad regional or systemic regulation of stem cells.
The
non-specialized niche can alternatively be considered a mesenchymal niche because of
its localization.
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Fig. 5 illustrates the concept of specialized and non-specialized niches among
representative stem cells. Both ISCs and Paneth cells form in a two-dimensional plane
on the basement membrane (Fig. 5A) to create a specialized niche that directly regulates
ISC proliferation. The lamina propria, found in villi and between crypts, contains actin
filaments, blood vessels, lymphatic vessels, peripheral nerves, macrophages, and
lymphocytes. It is interesting to know whether the lamina propria, as part of the
non-specialized niche, has an effect on ISCs. If this is the case, there is supposedly a
regional or systemic regulation of ISC number per crypt.
In the skin the specialized niche is less well understood than the non-specialized
niche.
Niche cells are presumably present in the bulge and basal layer on the basement
membrane (Fig. 5B, upper).
The dermis is the connective tissue containing fibroblasts,
endothelial cells, and nerve cells. Epidermal-dermal interactions are considered
important in development of the hair follicle, support of the hair cycle, and epidermal
wound repair.
However, the role of the dermis as a non-specialized niche requires
further study.
The seminiferous epithelium in the testis has the unique three-dimensional structure
consisting of spermatogenic cells and Sertoli cells (Fig. 5C). Spermatogonial stem cells
rest on the basement membrane between Sertoli cells. Like Paneth cells, Sertoli cells
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exhibit a large number of lysosomes. Sertoli cells function as the specialized niche by
secreting glial cell-derived neurotrophic factor, which induces self-renewal of
spermatogonia 97. The interstitium located between seminiferous tubes likely acts as the
non-specialized niche. Myoid cells lie beneath the basement membrane, and Leydig
cells, fibrocytes, vascular endothelial cells, macrophages, and neurons are present in the
interstitium.
All these cells could be members of the non-specialized niche, supporting
the previous proposal 98.
There is no specialized niche for HSCs. Instead, heterogeneous connective tissue or
stromal cells function as a non-specialized niche (Fig. 1). This conversely permits HSC
mobilization in the bone marrow. The basement membrane is located underneath the
vascular endothelium monolayer in bone marrow. The non-specialized niche where
HSCs reside can be regarded as lying under the basement membrane, similar to the
non-specialized niche in other tissues (Fig. 5D). The unusual anatomical sites of HSCs
in the non-specialized niche but not in the specialized niche suggest that HSCs may be
regulated in a manner that is fundamentally different from that of other stem cells. If so,
it may not be so crucial to specify niche cells and their anatomical sites for HSCs as it is
for other stem cells in order to understand niche function at the molecular level.
In E10.5 mouse embryos, HSCs emerge from subaortic patches underneath the
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basement membrane of the dorsal aorta
99
.
A positional relationship between HSCs
and a non-specialized niche may be maintained from embryonic to adult stages,
although the functional role of non-specialized niche may differ between the
aorta-gonad-mesonephros region and adult bone marrow.
It is noteworthy that in the
yolk sac, hemangioblasts, the common progenitors of blood cells and vascular
endothelial cells, likely arise from the mesodermal monolayer above the basement
membrane.
In this regard, the developmental niche in the yolk sac differs structurally
and functionally from that of the adult bone marrow.
Concluding remarks
A variety of niche components act together to regulate stem cells in a complex but
concerted manner. Whether stem cells are regulated in an instructive fashion is an
important issue in stem cell biology, particularly when we intend to manipulate stem
cells. Action of specialized niche factors is possibly more instructive than is that of
non-specialized niche factors. On the other hand, the regulation by non-specialized
niche may be broader and systemic than that by the specialized niche. The niche
supposedly maintains a quiescent state, determines cell fate and controls stem cell
mobility. To determine how specialized and non-specialized niches contribute to these
functions we must define molecular mechanisms underlying stem cell regulation in both
23
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steady and dynamic states, such as developmental or regenerative processes. Once we
know how the stem cells are regulated in physiological conditions or dysregulated in
pathological conditions, new therapeutic strategies targeting stem cells can be designed
that could be useful for stem cell-targeted cancer therapy or regenerative medicine.
24
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Acknowledgements
We thank Fumio Arai for critical reading of the manuscript. This work was supported by
Grants-in-Aid for Scientific Research (A) and (C), and Grants-in-Aid for Scientific
Research on Innovative Areas in Japan.
Authorship Contributions
Hideo Ema wrote the manuscript.
Toshio Suda wrote the manuscript.
Disclosure of Conflicts of Interest
The authors have no conflict of interest to declare.
25
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Figure legends
Figure 1
Stem cells in the bone marrow
HSCs are assumed to reside in endosteal and perivascular niches.
Osteoblasts mainly
constitute the endosteal niche. Mesenchymal stem cells (MSCs), perivascular stromal
cells, Cxcl12-rich reticular (CAR) cells, and sympathetic neurons together with
Schwann cells constitute the perivascular niche surrounding endothelial cells.
Macrophages and adipocytes may lie between these niches and influence HSC/niche
interaction.
Figure 2
Stem cells in the small intestine
Representative architecture of a crypt in the small intestine. Quiescent stem cells, or
label-retaining cells (infrequent cycling stem cells can be labeled with 3H thymidine or
BrdU for a long time), reside immediately above the uppermost Paneth cell at the fourth
position and express Bmi1. Cycling stem cells, or columnar basal cells, lie between
Paneth cells at the bottom of a crypt and express Lgr5.
Figure 3
Stem cells in the skin
Stem cells in the basal layer of the interfollicular epidermis replenish the multi-layered
33
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epithelium (spinous, granular, clear, and cornified layers). The hair follicle comprises
the cycling (epithelial hair germ cell) and non-cycling (bulge, isthmus, infundibulum,
and sebaceous gland) portion.
The bulge is separated into upper, middle, and lower
portions. Hair follicle stem cells in the bulge replenish hair, but also the sebaceous gland
and interfollicular epidermis in response to injury.
Figure 4
Stem cell number and niche
Stem cell number is regulated by a niche composed of cells, ECM, and soluble factors,
and also by positive and negative feedback loops from progenitors.
Autocrine and
paracrine loops may also regulate stem cell number.
Figure 5 Basement membrane and niches
Specialized and non-specialized niches are anatomically distinct in relation to the
basement membrane (bm). The specialized niche in close proximity to stem cells arrays
on the basement membrane in the epithelium. In concept, the specialized niche is
composed of particular cell types directly regulating survival and proliferation of stem
cells. The non-specialized niche, composed of numerous cell types widely distributed
among connective tissues, directly or indirectly regulates stem cells in a region. (A)
34
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ISCs and specialized niche cells, Paneth cells, form a monolayer of the epithelium on
the basement membrane . The lamina propria under the basement membrane may
function as the non-specialized niche.
(B) IFSCs and specialized niche cells in the
basal layer lie on the basement membrane of the epidermis.
as a non-specialized niche.
The dermis may function
(C) Spermatogonia, lying on the basement membrane, give
rise to spermatocytes and spermatids in the seminiferous epithelium of the testis.
Sertoli cells most likely serve as specialized niche cells. Leydig cells, myoid cells, and
vascular endothelial cells under the basement membrane may serve as a non-specialized
niche.
(D) In the bone marrow, the basement membrane is found underneath the
vascular endothelium. HSCs do not lie on the basement membrane with endothelial
cells. HSC lie among the non-specialized niche.
35
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Ema Fig. 1
Osteoblasts
Osteoclast
Macrophage
Perivascular
stromal cells
Sympathetic nerve
with Schwann cell
Adipocyte
MSC
CAR
Ang1
Wnt
TPO
SCF
Cxcl12
Endothelial cells TGFβ
36
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Ema Fig. 2
Wnt
Rspo1
+4 position
Bmi1+ stem cell
Paneth cell
Lgr5+ stem cells
BMP
37
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Ema Fig. 3
Interfollicular epidermis
Hair shaft
Epidermis
Sebaceous gland
Isthmus
Upper
Middle
Bulge
Lower
Dermis
Wnt
BMP
Hair germ
Dermal papilla
Shh
38
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Ema Fig. 4
Stem cell
Progenitor
Mature cell
Positive feedback
Niche
e
Negative feedback
39
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Ema Fig. 5
(A) Intestine
bm
Stem cell
Paneth cell
(B) Skin
bm
Stem cell
(C) Testis
bm
Spermatogonium Sertoli cell
Leydig cell
Myoid cell
(D) Bone marrow
bm
Stem cell
Niche cells
40
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Prepublished online July 11, 2012;
doi:10.1182/blood-2012-04-424507
Two anatomically distinct niches regulate stem cell activity
Hideo Ema and Toshio Suda
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