Stem cells are responsible for the growth, homeostasis
and repair of many tissues. The maintenance and sur
vival of stem cells is regulated by inputs from their local
microenvironment, often referred to as the ‘stem cell
niche’. The stem cell niche hypothesis was developed
in 1978 by Schofield, who proposed that stem cells
reside within fixed compartments, or niches, which
are conducive to the maintenance of definitive stem
cell properties1. Thus, the niche represents a defined
anatomical compartment that provides signals to stem
cells in the form of secreted and cell surface molecules
to control the rate of stem cell proliferation, determine
the fate of stem cell daughters, and protect stem cells
from exhaustion or death.
Elegant experiments in model organisms such as
worms and flies provided the first visualization of stem
cell niches in vivo, and subsequent genetic experi
ments have confirmed the importance of the niche in
regulating stem cell behaviour2–9. Recently, new tools
for labelling stem cells in situ have also facilitated the
localization and characterization of stem cell niches
in mammalian tissues10–15. In addition to providing
concrete evidence that niches are essential for proper
stem cell function, these studies have revealed that stem
cell niches are as varied as the stem cells they support.
Moreover, recent work indicates the existence of dis
tinct functional classes of niche, each specialized to
sustain the unique functions of particular tissues.
Finally, increasing evidence implicates deregulation of
the stem cell niche as a proximal cause of many path
ologies associated with tissue degeneration16, ageing17–20
As discussed below, studies in model organisms such
as Drosophila melanogaster and Caenorhabditis elegans
have revealed several features of stem cell niches that
are important for controlling stem cell behaviour. First,
signals that emanate from the niche regulate stem cell
selfrenewal, survival and maintenance2–3,5–7. Second,
the particular spatial relationship between stem cells
and support cells can polarize stem cells within the niche
to promote asymmetric stem cell divisions25,26. Third,
adhesion between stem cells and supporting stromal cells
and/or the extracellular matrix (ECM) anchors stem cells
within the niche in close proximity to selfrenewal and
survival signals27,28. Because recent developments have
facilitated the localization and visualization of stem cells
within mammalian tissues in vivo, it is becoming clear
that these key features of stem cell niches are also used
in more complex stem cell systems. Thus, the stem cell
niche provides structural support, trophic support, topo
graphical information and the appropriate physiological
cues to regulate stem cell function in both invertebrate
and vertebrate organisms (FIG. 1).
In this review, we discuss current concepts and
questions surrounding stem cell niches and their role
in regulating tissue maintenance and repair. Stem cells
hold tremendous potential to reveal fundamental mecha
nisms of cell fate specification and tissue growth, as well
as to stimulate novel approaches for tissue repair and
replacement. Yet one of the largest hurdles to the better
understanding of these cells and their use in regenera
tive medicine is the establishment of ex vivo systems that
support normal stem cell function — including self
renewal and appropriate lineagespecific differentiation.
*Laboratory of Genetics,
The Salk Institute for
La Jolla, CA 92037, USA.
‡Section on Developmental
and Stem Cell Biology,
Joslin Diabetes Center, and
Harvard Stem Cell Institute,
An anatomical structure,
including cellular and acellular
components, that integrates
local and systemic factors to
regulate stem cell proliferation,
differentiation, survival and
A type of cell that contributes
to the structure and connective
tissue aspects of an organ.
No place like home: anatomy and
function of the stem cell niche
D. Leanne Jones* and Amy J. Wagers‡
Abstract | Stem cells are rare cells that are uniquely capable of both reproducing themselves
(self-renewing) and generating the differentiated cell types that are needed to carry out
specialized functions in the body. Stem cell behaviour, in particular the balance between
self-renewal and differentiation, is ultimately controlled by the integration of intrinsic factors
with extrinsic cues supplied by the surrounding microenvironment, known as the stem cell
niche. The identification and characterization of niches within tissues has revealed an
intriguing conservation of many components, although the mechanisms that regulate how
niches are established, maintained and modified to support specific tissue stem cell
functions are just beginning to be uncovered.
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Nature Reviews | Molecular Cell Biology
A porous, or spongy, type
of bone that is filled with red
bone marrow, which appears to
be enriched for HSCs in adults.
A cell that is responsible for
bone formation and
The site of spermatogenesis in
the testis. The tubules are lined
with spermatogonial stem cells
and spermatogonia that will
eventually progress through
meiosis and differentiate into
mature spermatozoa. Somatic
Sertoli cells also line the
tubules and support
spermatogenesis by promoting
germ cell proliferation and
only by uncovering the intimate relationship between
stem cells and their surroundings can we hope to achieve
the necessary insights that will enable the development
and use of such systems.
Stem cell niches
To understand how the local microenvironment can
protect stem cells and influence their behaviour, it is first
necessary to determine where stem cells reside. Identifying
and characterizing stem cell niches has been complicated
by the fact that stem cells are extremely rare and, in many
cases, specific markers allowing the definitive identifica
tion of stem cells in vivo are lacking. nonetheless, much
progress has recently been made in identifying stem cell
niches, especially within mammalian tissues. For example,
many haematopoietic stem cells (HSCs) reside along the
endosteal surface of trabecular bone in close proximity to
both boneforming osteoblasts and the endothelial cells
that line blood vessels13,15,29. HSCs can leave this niche,
enter the circulation and return to the niche, and their
proximity to endothelial cells may facilitate mobilization
from the bone marrow into the circulation30. neural stem
cells (nSCs) can be found in two different locations in the
brain: within the subventricular zone of the hippocampus
and in the olfactory bulb. In both niches, nSCs are located
adjacent to endothelial cells, similar to HSCs10,11. Such
close association of stem cells with the tissue vasculature
could be important to expose these cells to systemic factors
that may promote their survival, regulate selfrenewal and
differentiation potential, and/or communicate ‘damage’
signals to activate their proliferation.
Epithelial stem cells reside within a specialized region
of the outer root sheath of the hair follicle, known as the
follicular bulge. These multipotent stem cells can contri
bute to the regeneration of the hair follicle and sebaceous
glands, as well as the interfollicular epidermis14, although
they do not appear to be necessary for normal, homeo
static replacement of epidermal cells31–33. Stem cells that
repopulate the interfollicular epidermis, known as basal
keratinocytes, are found at the base of the epidermis,
immediately above a basement membrane that separates
them from the underlying dermis34. within the mam
malian small intestine, gut stem cells reside at the base of
intestinal crypts and divide to produce daughter cells that
differentiate as they migrate upwards towards villi
that extend into the intestinal lumen35. Although intestinal
stem cells (ISCs) were initially thought to reside immedi
ately above Paneth cells in the crypts (at position +4)36,
recent lineage tracing analysis has instead revealed that
their activity tracks to a novel population of crypt base
columnar cells (CBCs) that are marked by the expression
of lGR5 (leurichrepeatcontaining Gproteincoupled
receptor5) and are interdigitated between Paneth cells37.
Spermatogonial stem cells (SSCs) maintain spermato
genesis throughout the lifetime of adult males. SSCs are
located adjacent to the basement membrane along the
periphery of the seminiferous tubules of the testis38. Recent
studies have demonstrated, however, that the distribu
tion of undifferentiated spermatogonia, which probably
includes SSCs, is not random. These cells appear to pre
ferentially localize close to the vascular network and inter
stitial cells that exist between adjacent tubules39. Skeletal
muscle stem cells, a subset of musclefibreassociated
satellite cells, are found along the length of the myofibre,
in close contact with the myofibre plasma membrane
and beneath its basement membrane40–42. Interestingly,
it appears that tissue stem cells often reside in locations
where they are relatively protected from damage (such as
environmental toxins35 or ultraviolet irradiation14) com
pared with the more differentiated cells that they produce.
Specific features of each of these niches are discussed in
more detail below (TABLE 1).
Components of stem cell niches
Prototypical stem cell niches, including those that sup
port blood, germline and epithelial follicular bulge stem
cells, have revealed several physical and functional char
acteristics that appear to be hallmarks of a stem cell niche
(FIG. 1). By synthesizing data from numerous systems, we
can generate a hypothetical ‘parts list’ for stem cell niches,
including: the stem cell itself; stromal support cells that
interact directly with the stem cell and with each other
through cellsurface receptors, gap junctions and soluble
factors; ECM proteins that provide structure, organiza
tion and mechanical signals to the niche; blood vessels
Figure 1 | components and functions of stem cell niches. The niche is a complex and
dynamic structure that transmits and receives signals through cellular and acellular
mediators. This schematic depicts a hypothetical niche composite, which summarizes
known components of previously described mammalian and non-mammalian niches:
the stem cell itself, stromal cells, soluble factors, extracellular matrix, neural inputs,
vascular network and cell adhesion components. It is important to note that although
many niche components are conserved, it is unlikely that every niche necessarily
includes all of the components listed. Instead, niches are likely to incorporate a
selection of these possible avenues for communication, specifically adapted to the
particular functions of that niche, which might be to provide structural support, trophic
support, topographical information and/or physiological cues.
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The authors would like to thank H. Mikkola, D. Laird, N. Geijsen
and members of the Jones and Wagers laboratories for advice
and comments on the manuscript. D.L.J. is supported by an
Ellison Medical Foundation New Scholar Award, the American
Federation for Aging Research, the G. Harold and Leila Y.
Mathers Charitable Foundation, and a National Institutes of
Health grant. A.J.W. is supported by a Burroughs Wellcome
Fund Career Award, a Pilot Grant from the Paul F. Glenn
Laboratories, and by the Harvard Stem Cell Institute. We apolo-
gize to those colleagues whose work has not been cited directly
owing to space limitations.
c-kit | CXCR4 | DKK1 | LGR5 | SLF | SOX17
D. Leanne Jones’s homepage: http://www.salk.edu/faculty/
Amy J. Wagers’s homepage: http://www.joslinresearch.org/
all linkS are acTive in The online pdf
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