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Department of Biochemistry and Molecular Biology, The University of Maryland School of Medicine, USA
Department of Dermatology, The University of Maryland School of Medicine, USA
Department of Reproductive Biology, The University of Maryland School of Medicine, USA
d
Department of Microbiology and Immunology, The University of Maryland School of Medicine, USA
e
The Marlene and Stewart Greenebaum Cancer Center, The University of Maryland School of Medicine, USA
f
Life Technologies, Inc. Primary and Stem Cell Culture Systems, Frederick, MD, USA
g
Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, USA
b
c
a r t i c l e
i n f o
Article history:
Received 2 May 2012
Accepted 10 July 2012
Available online 20 July 2012
Keywords:
Stem cell
Hair follicle
Interfollicular stem cell
Epidermis
Keratinocyte
a b s t r a c t
Background: The epidermis is an important protective barrier that is essential for maintenance of life.
Maintaining this barrier requires continuous cell proliferation and differentiation. Moreover, these processes
must be balanced to produce a normal epidermis. The stem cells of the epidermis reside in specic locations
in the basal epidermis, hair follicle and sebaceous glands and these cells are responsible for replenishment of
this tissue.
Scope of review: A great deal of effort has gone into identifying protein epitopes that mark stem cells, in identifying
stem cell niche locations, and in understanding how stem cell populations are related. We discuss these studies as
they apply to understanding normal epidermal homeostasis and skin cancer.
Major conclusions: An assortment of stem cell markers have been identied that permit assignment of stem cells
to specic regions of the epidermis, and progress has been made in understanding the role of these cells in normal
epidermal homeostasis and in conditions of tissue stress. A key nding is the multiple stem cell populations exist
in epidermis that give rise to different structures, and that multiple stem cell types may contribute to repair in
damaged epidermis.
General signicance: Understanding epidermal stem cell biology is likely to lead to important therapies for treating
skin diseases and cancer, and will also contribute to our understanding of stem cells in other systems. This article
is part of a Special Issue entitled Biochemistry of Stem Cells.
2012 Elsevier B.V. All rights reserved.
2428
Fig. 1. Structure of the hair follicle and the epidermis. The schematic shows hair follicle structures including the infundibulum, junctional zone, isthmus, sebaceous gland, bulge,
bulb and hair shaft. The epidermal layers (basal, spinous, granulate and cornied) are also shown. The interfollicular epidermis is the stratied epidermis located between the
hair follicles. The text describes various regions of these structures where specic stem cell populations, identied by specic markers, are located.
terminal structure, the nucleus and all other organelles are destroyed
[57]. Ultimately, these cells are shed from the skin surface as the terminal event in differentiation. This tissue includes three major functional
zones, the proliferative cells of the basal layer (which include the
stem cells), partially differentiated cells of the spinous and granular
layers which are viable but non-proliferating, and the terminal differentiated dead cells of the cornied layer. Regulation of cell survival is important in each of these zones (Fig. 1). The molecular processes that
control differentiation are complex and involve many gene products
[36,38].
Keratinocyte stem cells (KSC) are proliferation units that display limited and slow division, can self-renew and are responsible for generating
the various lineages present in the mature tissue [17,18,21,56,127129].
These were initially identied as label-retaining cells [16,19,20]. Current
studies identify three populations of KSCs in epidermis. These include
the interfollicular (IF) epidermal stem cells in the epidermal basal
layer, the hair follicle (HF) stem cells of the bulge and the sebaceous
gland (SG) stem cells located immediately above the hair bulge. The IF
epidermis is the skin surface located between hair follicles. Under normal conditions these stem cell populations appear to function independently to produce the IF epidermis, hair follicle and sebaceous gland.
However, recent studies suggest that each of these cell populations can
function to replicate any skin structure [46,73], which may be particularly important when the epidermis is stressed.
Specic differences are evident in the microanatomy and composition of the stem cells between mice and humans. These differences
emphasize the importance in distinguishing among animal models
when studying epidermal stem cells. For instance, the hair bulge is a
very distinct structure in the follicle and is a primary source of epidermal stem cells in the mouse, while in humans the hair bulge is less
distinct and IF stem cells appear to be the more abundant stem cell.
However, studies of label-retaining cells indicated that human hair
follicle stem cells like those in the mouse can also be found in the
bulge-like structure [79,98].
Stem cells, located in the IF epidermis in the basal layer, are an important population of cells involved in maintaining the IF epidermis.
Barrandon and Green characterized differences in proliferative potential of keratinocyte cultures prepared from the human epidermis [11].
Three populations of cells were identied and called holo-, para- and
metaclones. The holoclones give rise to the largest colonies in clonal
growth assays and are rich in markers of the epidermal basal layer, including 1-integrin [69]. Subsequent studies reveal that these cells are
rich in 6-integrin and express low levels of CD71 (transferrin receptor) [128,129]. 6-integrinbri/CD71 dim cells display many stem cell features, including quiescence and long-term growth capacity (Table 1)
[74,128,129]. These cells are generally detected at the downward tip
of the rete ridges. However, another population of cells, that are
1-integrin+/MCSP (melanoma chondroitin sulfate proteoglycan)+/
Table 1
Distribution of stem cell markers in human and murine epidermis.
Marker
Location
References
Species
6bri/CD71dim
1+/MCSP+/Lrg1+
Survivin+
Lgr6+
CD133 (prominin)
CD200+
K15+
CD200+/CD34/K15bri
CD200+/CD34/K15dim
CD34+
K15 Promoter
K19
6dim/MTS24+/Lrig1+
Sca-1+
Lrig1+
Lgr6+
Blimp1+
NGFRp75, nestin, Oct-4
IF epidermis
IF epidermis
IF epidermis
IF epidermis
IF epidermis
HF (bulge)
HF (bulge)
HF (bulge)
HF (bulge)
HF (bulge)
HF (bulge)
HF (bulge)
HF (isthmus)
HF (infundibulum)
HF (isthmus)
SG (isthmus)
SG
MSC (dermis)
Neural crest (bulge area)
Cancer stem
Cancer stem
[74,128,129]
[65,66,71]
[80]
[133]
[141]
[98,99]
[88]
[64]
[64]
[22]
[88,118]
[85]
[96]
[67]
[65]
[112]
[63]
[76]
[140]
[100]
[106]
Human
Human
Human
Mouse
Human
Human
Mouse
Human
Human
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Human
Mouse
CD133+
6bri/1dim/CD34bri
6bri/1dim/CD34dim
Lrg1+, are present in the upper segment of the rete ridge and these
share stem cell properties [65,66,71]. Additional markers of these cells
have also been identied, including survivin [80]. The existing information suggests that IF epidermal stem cells are randomly distributed in
the basal layer and represent 1% to 7% of the basal cell population. The
1% level was determined by labeling experiments using human epidermal organotypic skin cultures [91] and the higher values were determined based on detection of 6-integrinbri/CD71 dim human cells
[129]. It is interesting that neonatal foreskin includes more stem cells
(7%) than skin derived from adults (5%) [128,129]. The localization of
the murine IF epidermal stem cells is controversial. Evidence suggests
that Lgr6 + cells, present in the HF, near the infundibulum, serve as a
stem cell reservoir for the murine IF epidermis [133]. CD133 is a putative marker of the murine dermal papilla [141].
Various other proteins have also been identied that help to distinguish epidermal stem cells. For instance, connexin43 (Cx43) a gap junction protein is absent in 10% of human basal keratinocytes which also
exhibited clonal ability, small size and low granularity. Cx43dim cells
also helped distinguish p63+/ABCG2+/1-integrin+ label-retaining
cells in the human limbal epithelium [31]. Desmoglein3 (Dsg3) is another intercellular junction protein that may be a useful marker for
distinguishing epithelial stem cells. High 1-integrin expressing
human keratinocytes have been shown to express low levels of Dsg3
and exhibit greater long-term proliferative capacity in vitro than
integrin 1hi/Dsg3hi cells. The 1hi/Dsg3lo cells isolated from the adult
human palm show comparable clonogenic ability to 6hi/CD71lo cells
[121,122]. Some evidence suggests that CD146, melanoma cell adhesion
molecule (MCAM), may also distinguish stem cells. For example,
CD146lo selection, in conjunction with selection for other markers, including CD200+, CD24lo, CD34lo, CD71 lo, isolates human hair follicle
cells with high colony-forming efciency [98]. Other markers that
have been studied include human EGFR lo (epidermal growth factor
receptor) cells which undergo long-term expansion and produce a
stratied epidermis in models of skin reconstruction [45]. Low major
histocompatibility complex, MHC Class I-HLA expression is observed
in pluripotent stem cells and also in a subpopulation of basal human
keratinocytes [83].
2. Two models of epidermal stem cell amplication
In addition to holoclones, Barrandon and Green identied other
dividing cells called paraclones, which give rise to abortive colonies
that differentiate after only limited proliferation and meroclones
which are intermediate in morphology and proliferative capacity [11].
Based on these and other ndings, it has been theorized that the IF epidermis includes a mixture of proliferating cells consisting of holoclones
and paraclones [11]. The holoclones are thought to correspond to the
label-retaining stem cell population and the paraclones to the transient
amplifying cells. These cells are distinguished based on differences in
label-retention [28], cell surface marker expression, proliferation frequency, and ability to grow as clones in culture [11,11,28,64,96,98,117].
In murine epidermis cell populations have been distinguished as epidermal stem cells which are label-retaining and occasionally give rise to an
identical daughter stem cell (symmetrical division) and a transient
amplifying cell (asymmetrical division). Unlike the epidermal stem cell,
the transit amplifying cell divides rapidly and, after several rounds of
cell division, undergoes terminal differentiation.
However, fate mapping experiments question the existence of
transient-amplifying cells [34,68]. These studies used inducible genetic
labeling to track progenitor cells in murine tail epidermis for one year.
Results showed that the average number of basal layer cells per clone
increases in a linear fashion with time and does not follow an epidermal proliferation unit pattern which would be expected if transient
amplifying cells were present. Since the clones remained cohesive and
expand in size over time, this suggests that only one type of proliferative
stem cell exists that undergoes an unlimited number of symmetrical
2429
2430
and neck squamous cell cancer stem cells [101]. CD24 is a glycoprotein and CD24 neg expression is present in more primitive, or less
differentiated mammary stem cells, and is a marker of post-mitotic
human keratinocytes [15].
Basal cell carcinoma is restricted to areas of the epidermis with
hair, and the marker protein prole observed in BCC is consistent
with a hair follicle-origin of the tumors [109]. Moreover, mutation
in Ptch1, the Sonic hedgehog receptor, which is involved in hair follicle regeneration, is observed [8,75], and the level of Lgr5, a HF stem
cell marker, is increased in most BCCs [116]. These ndings strongly
suggest that HF stem cells give rise to BCC, although recent results
suggest that this model may be more complicated than previously
appreciated [55,123,139].
6. Other stem cells in the epidermis
Non-epithelial stem cells are also found in the epidermis. These include bone marrowderived stem cells (BMSCs) which are found in
the epidermis during epidermal regeneration. Several studies suggest
that BMSCs have the ability to derive both dermal and epidermal cells
during regeneration [10,24,29,35,42]. An alternative explanation for
such results is the demonstrated ability of BMSCs to fuse with other
cells in vitro. However, while ex vivo studies have demonstrated the
ability of BMSCs to fuse with keratinocytes [12], several studies
have shown that in vivo fusion does not occur [24,62,134] and that
BMSCs differentiate into epidermal cells [135].
7. Signaling proteins in epidermal stem cells
A requirement for stem cell survival is that the quiescent state be
tightly controlled. This involves a number of signaling cascades, some
of which are discussed here. The hair follicle utilizes sonic hedgehog
(Shh) and Wnt signaling to control cell function. Wnt/-catenin signaling regulates cell fate. Wnt is a secreted glycoprotein that binds
to Frizzled receptors to trigger a cascade that results in displacement
of GSK-3 from the APC/Axin/GSK-3 complex. In the absence of Wnt
signaling, -catenin is phosphorylated and targeted for degradation
by the APC/Axin/GSK-3 complex. In the presence of Wnt, Dishevelled is phosphorylated and activated and recruits GSK-3 from the
complex. This leads to -catenin stabilization and Rac1 nuclear translocation and recruitment of LEF/TCF DNA binding factors to activate
transcription [102]. Wnt signaling, via its impact on TCF3 transcription factor, is essential for maintenance of HF stem cells [48,84,144],
and blocking Wnt action causes cells to differentiate into keratinocytes
and sebocytes [78,95]. These ndings indicate that Wnt signaling
controls commitment of HF bulge cells in mouse to maintain the stem
state or permit entry into a differentiation pathway.
Sonic hedgehog (Shh) is a ligand that binds to its membrane-spanning
receptor, Patched (Ptc). Under resting conditions, Ptc binds to and inhibits
Smoothened (Smo), a transmembrane protein. The hedgehog signaling
complex is downstream of Smo. When Shh binds to Ptc, the inhibitor
impact on Smo is relieved and Smo becomes phosphorylated. Another
protein called Ci is then released and enters the nucleus to drive
expression of hedgehog target genes. Sonic hedgehog (Shh) is a
second important controller of HF bulge stem cells. Shh is a key
gene that is activated in order to organize dermal cells to form the
dermal papilla [104]. Inhibition of the Shh pathway during embryonic
development arrests the follicle at the hair bud stage after placode
formation and initial ingrowth [114]. Furthermore, inhibition of Shh in
adult skin prevents anagen hair growth [124].
Notch and EGFR signaling are also key pathways in the IF epidermis [47]. Notch signaling is pronounced in the basal layer of the epidermis with high activity in areas featuring stem cells [77]. Notch
signaling also drives keratinocyte differentiation as the cells depart
the stem cell niche [77]. In mouse epidermis differentiation and
maintenance of IF epidermis are balanced by the opposing actions
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