Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
doi:10.1093/hmg/ddn086
R54–R59
Skin and hair: models for exploring
organ regeneration
Benjamin D. Yu , Anandaroop Mukhopadhyay and Crystal Wong
Division of Dermatology, Department of Medicine, University of California, San Diego, CA 92093, USA
Received February 9, 2008; Revised and Accepted March 12, 2008
Skin is an excellent model to study the basic biology of organ regeneration and translational approaches to
regenerative medicine. Because of the accessibility of the skin, a long history of regenerative approaches already
exists. Identifying the commonalities between skin regeneration and the regeneration of other organs could provide major breakthroughs in regenerative medicine. The hair follicle represents a miniature organ with readily
accessible stem cells, multiple cell lineages, and signaling centers. During the normal lifespan of a human,
this miniature organ regenerates itself more than 10 times. The cells responsible for this remarkable process
are called bulge stem cells. A plethora of molecular and genetic tools have been developed to follow their fate
and to explore their ontogeny. Major advances have been made toward understanding the normal cell fate of
bulge stem cells and their developmental plasticity. Recent studies suggest the epidermis and hair may have
an untapped potential to form other organs. Understanding the mechanisms that regulate adult stem-cell proliferation is a major goal for regenerative medicine. In the hair follicle, pharmacologic agents, recombinant proteins,
and artificial cell-permeable proteins have been developed to manipulate the proliferation of the quiescent bulge
stem cells. These advances illustrate a potential roadmap for regenerative medicine using molecular tools developed for skin biology to promote organ regeneration by manipulating adult stem cells in situ.
INTRODUCTION
Many of today’s expectations for regenerative medicine
including tissue and organ replacement have been in practice
for skin treatments for almost three thousand years. The first
documented allo- and autologous skin grafts were performed
in ancient India (600 B.C.) and later in Europe (1400 –
1800s) to repair injuries and tissue destruction caused by
syphilis (1,2). During World War II, the first tissue banks
were established by the US Navy to cryopreserve human
skin for the treatment of burns. Ex vivo expansion of skin
cells called keratinocytes was developed in the 1970s, and in
1998, the FDA approved the first tissue-engineered skin for
diabetic ulcers (3). More recently, gene replacement therapy
has been used successfully to treat a life-threatening skin congenital disorder caused by laminin (LAMB3) deficiency (4).
Future skin regenerative therapies may have even broader
medical applications. Engineered skin grafts in mice are
capable of producing physiologic levels of hormones, such
as leptin (5), and replacing systemic deficiencies in plasma
proteins such as Factor VIII (6). These studies provide the
proof-of-concept that ectopic production of proteins in skin
grafts could provide an alternative approach to treating
human endocrine or hematological disorders. Advances in differentiating human embryonic stem (ES) cell into keratinocytes provide a possible avenue for genetic engineering of
human skin and a limitless source of tissue (7). The groundbreaking discovery of induced pluripotency in somatic cells
bring closer to reality patient-derived stem-cell treatments
for skin and many other disorders (8,9).
While these advances have many implications for producing
replacement cells, the prospect of producing replacement
organs seems far on the horizon. To regenerate an organ as
complex as a kidney or lung would likely be more difficult
than differentiating pluripotent stem cells to the correct
lineages. Adult stem cells have several advantages over ES or
induced pluripotent stem (iPS) cell transplantation for organ
regeneration (10). First, adult stem cells have likely undergone
most of the developmental steps necessary to regenerate an
organ. Secondly, delivery of ES or iPS cells to the precise
anatomical site for regeneration may be difficult. In contrast,
adult stem cells are already in niche environments and near
To whom correspondence should be addressed at: UCSD School of Medicine, 9500 Gilman Dr, MC-0741, La Jolla, CA 92093-0741, USA.
Tel: þ1 8585349426; Fax: þ1 8585349425; Email: [email protected]
# The Author 2008. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected]
Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
signaling centers that carry all the extrinsic information necessary for patterned growth. Thirdly, although new advances in
induced pluripotency greatly reduce the risk of cancer in transplanted ES or iPS cells, uncertainty about the risk of malignancy still exists because of genetic manipulation or because
of the inherent potential for ES and iPS cells to form teratomas.
Although adult stem cells appear to have advantages, there
are also limitations. The true developmental potential of most
adult stem cells in vivo is not known. A major limiting factor
is that adult stem cells are often rare in number and are quiescent, and thus manipulating adult stem cells to participate in
regeneration could prove to be a major obstacle.
The attributes that make the skin amenable to replacement
therapies also make it an excellent model to study the
biology of organ regeneration and the regulation of adult
stem cells. This review highlights recent advances in the
understanding of the cellular contribution and regulation of
the adult stem cells in the regeneration of the skin and hair.
ANATOMY AND DEVELOPMENT
OF EPIDERMIS AND HAIR
The skin is the largest organ of the human body (2 m2 in
surface area) (11). The epidermis is a stratified epithelium
that is constantly renewed by keratinocyte stem cells and transient amplifying progenitors located in the basal layer (Fig. 1A).
The upper layers of the epidermis are post-mitotic and undergo
progressive differentiation to form a barrier called the stratum
corneum. The stratum corneum can be detected toward the
end of the first trimester in humans and embryonic 16 (E16)
Figure 1. Anatomy of the epidermis and hair follicle. (A) The epidermis is a
stratified epithelium generated by basal keratinocyte progenitors. Rarely dividing epidermal stem cells (red) give rise to transient amplifying cells (pink).
Transient amplifying cells can divide to produce more transient amplifying
cells or to generate a post-mitotic keratinocyte. Post-mitotic keratinocytes
undergo multiple steps in differentiation including altered composition of
intermediate filaments called keratins. As keratinocytes mature, they
produce barrier proteins, flatten and ultimately become incorporated into the
cornified envelope. (B) The hair follicle is an invaginated organ. At
the base of the hair follicle is a transient amplifying population called the
matrix. The matrix gives rise to cells, which become incorporated into the
hair shaft and supporting cells. Another supporting layer of cells is called
the outer root sheath (ORS). These cells play a paracrine role in hair growth
and shape. The upper portion of the hair follicle contains organ stem cells
called bulge stem cells. Bulge cells are similar to ORS cells and are situated
in a nexus where nerve, muscles, sebaceous gland and melanocytes can be
found in close proximity. Arrows indicate cell division that gives rise to differentiated lineages or that give rise to self (self-renewal).
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days in mice, as it becomes impermeable to aqueous dyes
(12). Cells of diverse embryonic origins ultimately occupy the
postnatal epidermis including melanocytes, Merkel cells, epidermal Langerhan and T-cells (13). This collective unit serves
as a physical, innate and adaptive immune barrier (14). In
addition the skin functions as a major endocrine organ and is
a major platform for neural sensory input (15). While this
review focuses on epithelial stem cells, other cellular components of the skin are likely renewed by separate stem-cell
compartments and are reviewed elsewhere (16).
The skin is home to many mini-organs (also referred to as
appendages or adnexal structures) including hair, nails,
mammary, sebaceous and sweat glands. Like the epidermis,
the hair follicle is a stratified epithelium but is concentrically
arranged (Fig. 1B). The innermost layers (medulla, cortex,
cuticles, inner root sheath, companion) are derived from a
transient population of cells, collectively called the matrix
(17,18). An outer layer called the outer root sheath (ORS)
shares more similarity to the epidermis and plays an indirect
paracrine role in modulating hair growth and shape (18,19).
Development of hair follicles can be first detected at the end of
the first trimester in humans (13) and at embryonic age 14.5
(E14.5) in mice (20,21). At this stage, the hair follicle anlage is
called a placode, a local epithelial thickening that is induced by
the dermal mesenchyme (Fig. 2A) (22). Transformation of
Figure 2. Comparison of hair development and fates during normal development, hair cycling and post-wounding. (A) Differences between hair formation
during neogenesis (top) and the hair cycle (bottom). Neogenesis of hair begins
from an early placode and progresses to a mature hair follicle (left to right).
Shown in tan are Lhx2-positive cells in the hair follicle progenitors and
later in the bulge. Regenerative hair growth during a hair cycle starts from a
telogen or ‘resting’ hair follicle and results in a mature hair follicle, which
is indistinguishable from hair generated by neogenesis. (B) Differences
between cell fates in normal (left) and wounded (right) skin. Normally, the
hair follicle (red) and the epidermal unit (blue) are two independent selfsustaining tissue compartments. After wounding, cells from the hair follicle
are recruited to the epidermis and undergo epidermal differentiation.
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Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
the placode into an invaginated bud and subsequently into an
increasingly complex structure results from reciprocal interactions
between the mesenchyme and epithelium. Localized secretion
of growth factors by specialized cells called organizing centers
helps creating patterned growth during organogenesis.
Many of the molecules produced by the hair follicle epithelium and mesenchyme have now been identified including
ectodysplasin, fibroblast growth factors (FGF1, 2, 5, 7, 10,
18), WNTs (WNT3, 3a, 4, 5a, 10a, 10b, 11), hedgehog
family members (Shh, Ihh) and bone morphogenetic proteins
(BMP2, 4, 6, 7, 8a) (21,23 – 26). Surprisingly, the signals
and early morphogenesis of the hair placode are similar in
the development of other epithelial organs including nail,
teeth, mammary glands, and even feathers (27,28). Genetic
defects in one of these signaling pathways often result in
defects in multiple ectodermal organs. For example, in
ankyloblepharon ectodermal dysplasia clefting or ectrodactyly
ectodermal dysplasia and facial clefting (29) syndromes,
mutations in p63 disrupt hair, teeth, nail, and limb development (30,31). The early stages of hair follicle morphogenesis
from an uncommitted epithelium are often defined as
neogenesis to distinguish its de novo development from the
cyclic regenerative growth that occurs during the hair cycle
(Fig. 2).
REGENERATION OF THE HAIR AND EPIDERMIS
The adult hair follicle is a professional regenerating organ. In
an average human lifespan, the hair follicle regenerates more
than 8 to 10 times. During every hair cycle, a cellular
program is activated which generates the cells necessary to
regenerate the hair follicle. This period of hair growth
(called anagen) is followed by a stage called catagen, when
most of the follicular epithelium undergoes apoptosis and
regresses (32,33). Following catagen, the remaining upper
hair follicle enters a quiescent stage called telogen. In
humans, this quiescent period can last for 1 – 4 months and
is followed by 2 – 8 years of hair growth (11).
The source of cells for cyclic regeneration of the hair follicle
is the bulge, a specialized region of the ORS in the upper hair
follicle (Figs 1 and 2). Bulge cells are the definitive adult stemcell population of the hair follicle. Their contribution to the
lineages of the hair follicle has been demonstrated by several
approaches to follow the fate of bulge cells using retention of
nucleoside analogs or fluorescent labels (34,35) and genetic
markers activated by Cre recombinase (36). These studies
show that bulge stem cells under normal conditions, give rise
exclusively to the hair follicle. Transplantation of isolated
bulge stem cells shows that they have the developmental potential to generate all lineages of the hair follicle including a new
stem-cell compartment (37).
Quiescent adult stem cells can also be found in the
epidermis which have tremendous growth potential in vitro
(38 – 40). In vivo cell-fate studies demonstrate clonal populations giving rise to columns of stratified epidermis called
epidermal-proliferation units (EPUs) (Fig. 2B) (41 – 44).
These studies also show that EPUs do not intermix with
cells in the hair follicle unit. Hence, adult stem cells in both
the hair and epidermis have many of the expected properties
of stem cells including longevity and infrequent cell divisions,
and under normal conditions, the two compartments function
as distinct self-renewing units.
DEVELOPMENTAL PLASTICITY OF THE HAIR
IN WOUND REPAIR
It has long been observed that following wounding or severe
skin burns, new epidermal growth begins around hair follicles.
Two recent studies directly examine how either hair follicle
cells (including bulge stem cells) or the bulge stem cells themselves contribute to wound regeneration (36,45). Fate studies
show that both bulge cells and other hair follicle cells are
recruited to repopulate the wounded area (Fig. 2B). However,
while the descendents of the bulge stem cells are eventually
eliminated from the wound site, other cells from the hair follicle
remain in the epidermis for at least 16 weeks. These findings
suggest that a non-bulge stem lineage (possibly the contiguous
ORS layer) form a permanent residence in the epidermis.
Another form of wound repair has been observed where
both new epidermis and new hair follicles develop in the
wound site. A recent study shows that the new hair follicles
that develop in the wounded area morphologically mimic
embryonic hair development (neogenesis) (46). Molecular
studies show many of the same signaling molecules that are
involved in embryonic neogenesis are expressed in this adult
neogenesis. Like embryonic hair development, regeneration
of new hair follicles requires WNT signals. Experimental
expression of a secreted WNT antagonist, Dkk1, blocks new
hair follicles from forming in the wound area. Wound
closure by new epidermis is not affected by the inhibition of
WNT, indicating that early recruitment of cells to the wound
site is independent of WNT. The source of cells that give
rise to new epidermis and new hair follicles is not yet
known but do not appear to arise from the bulge.
Observations from wound regeneration in the adult skin
indicate a high degree of developmental plasticity. In the
embryo, the epidermal decisions to produce a hair, sweat
gland, or mammary gland are determined by the underlying
mesenchyme (47). Positional information contained within
the embryonic mesenchyme is believed to instruct the epidermis to form the correct type of hair follicle or feather for the
anatomical site (e.g. scalp instead of a body hair). In the adult,
the signals produced by the mesenchyme that instruct epidermal patterning are undoubtedly complex and may rely on the
positional memory of the fibroblast (48). In light of the similarities between embryonic and adult neogenesis, it is critical
to understand the similarities between regenerative and
embryonic mechanisms that regulate organ size and shape.
ONTOGENY AND REGULATION OF BULGE
STEM CELLS
When and how bulge stem cells become specified is becoming
more clear. Many bulge stem-cell markers, keratin 15 (K15),
CD34, C/EBP-alpha, and MTS24 are expressed several days
after the start of hair development, suggesting that the bulge
stem cells might not participate in hair growth until after
neogenesis (29,35,49 – 53). Recently, additional molecular
Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
markers have been identified in bulge stem cells through
microarray studies (35,52,53). These genes are expressed
much earlier in hair development and suggest that bulge
stem cells or their progenitors may participate earlier during
neogenesis. One such gene, LIM homeobox 2 (Lhx2), is
expressed in the embryonic placode and at later stages in the
postnatal bulge (54). Lhx2 is a LIM homeodomain transcription factor, which represses interfollicular differentiation.
While it is not known whether Lhx2-positive cells in the
placode become the bulge postnatally, it is tempting to speculate that primitive progenitors of the hair organ later become
its definitive adult stem cells.
The major decision of an adult stem cell is whether or not to
divide. Bulge stem cells can be triggered to divide synchronously using a variety of exogenous stimuli including ‘plucking’ (also called depilating), drug treatment and, as discussed
above, skin wounding (55 – 57). The kinetics of cell cycle
re-entry differ between stimuli. After depilation, it is known
that the bulge stem cells re-enter DNA synthesis (S-phase)
in 24 h and return to quiescence after 48 h. Pharmacologic
agents including phorbol esters, cyclosporine, trichostatin,
and retinoic acids have all been used to stimulate the hair
cycle in mice as well as recombinant proteins such as
Noggin and Shh mimetic molecules (58,59). Exogenous
stimuli may mimic the normal signals that activate bulge stemcell proliferation. Noggin is the primary candidate molecule
for initiating the hair cycle as it is expressed at the beginning
of anagen (60). Noggin is a secreted antagonist of BMPs (bone
morphogenetic proteins). Experimental inhibition of BMP signaling by over-expression of Noggin or by inactivation of the
Bmp receptor 1a (Bmpr1a) results in premature activation of
the hair cycle (61,62). These findings suggest that regulating
BMP activity plays a major role in determining bulge stemcell quiescence and proliferation.
The transition of cells from quiescence into the cell cycle is
characterized by the sequential activation of cyclin-dependent
kinases (CDKs) by D and E-type cyclins (Fig. 3) (63). Injection of cell-permeable CDK inhibitors, TAT-p16INK4a or
TAT-p27KIP in depilated hair follicles block initiation of the
hair cycle, indicating that activation of CDK4/6, targets of
p16INK4a, is required for triggering bulge stem-cell proliferation. Normally, D-type cyclins (Cyclin D1, D2, D3) trigger
the activation of CDK4 and CDK6. Signals known to stimulate
the hair cycle including WNT and SHH are also known to
induce expression of D-type cyclins and could provide the
signal that determines whether bulge stem cells re-enter the
cell cycle (64,65). Microarray data demonstrates that multiple
WNT antagonists are expressed in quiescent bulge stem cells
and suggest that inhibition of WNT signaling may be critical
in maintaining quiescence. Regulation of CDK4 transcription
has also recently been described (57). CDK4 expression is
silenced by Nfatc1, a NFAT transcription factor regulated by
calcineurin. Nfatc1 is highly expressed in quiescent bulge
stem cells. Importantly, BMP4 can activate the Nfatc1 promoter and thus provide a second mechanism to control bulge
stem-cell proliferation. Regulation of CDK4 turnover has
also been reported but their role in regulating adult stem-cell
proliferation is unknown (66).
Involvement of BMPs in CDK4 regulation and WNTs in
cyclin D induction suggests regulation of both pathways are
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Figure 3. Regulation of CDK4 expression and activation by early anagen
signals. (A) CDK4 transcription is repressed by a BMP(bone morphogenetic
protein)-NFATc1 pathway. Expression of Noggin or loss of BMP allows
CDK4 to be expressed. Cyclin D1 is induced by SHH and/or WNT, which
binds and activates CDK4. The experimental inhibition of Cyclin D– CDK4
interaction by TAT-p16INK4a prevents activation of proliferation and the hair
cycle. (B) Differences between refractory (top) and permissive (bottom)
resting hair follicles. During refractory states, high levels of BMP2 and
BMP4 expressed by the dermis and subcutaneous fat control the refractoriness
of the hair follicle to spontaneous cycling. In the presence of BMPs, CDK4
transcription is silenced, which prevents the bulge from responding to cyclin
D expression. During permissive states, BMP antagonists overcome BMP
levels in the milieu and CDK4 repression. Production of CDK4 protein
allows the bulge stem cells to respond to anagen-inducing stimuli such as
SHH and WNT and activates a new hair cycle.
necessary to activate bulge stem-cell proliferation (Fig. 3B).
BMP2 and BMP4 expression by the surrounding dermis and
subcutaneous fat has recently been shown to contribute to
the refractoriness of the hair follicle to re-enter anagen (67).
Refractoriness by BMP could render bulge stem cells unresponsive to Cyclin D by downregulating CDK4 expression.
The role of other CDKs in the hair cycle is not known, but
it is likely they also have a role in regulating bulge stem-cell
proliferation since mice deficient in CDK4 have not been
reported to have hair loss phenotypes (68). Finally, whether
dual regulation of CDK4 expression and its activation is
common among adult stem cells in other organs remains to
be determined.
CONCLUSION
Therapeutic applications using pluripotent and adult stem-cell
technology are edging closer to reality. Patient-derived pluripotent stem cells are poised for hundreds of potential cell
replacement therapies. While organ replacement may appear
a more distant reality; lessons from studying regeneration of
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Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
epidermis and hair suggests that reprogramming ectoderm to
generate an array of ectodermal organs may be possible.
Organ replacement might also rely on mobilizing resident
adult stem cells. Like re-stimulating new hair growth, stimulating adult stem-cell proliferation and numbers could be
another molecular tool to induce regeneration in other
organs. Together, pluripotent and adult stem cell advances
usher in a new era of medicine that may provide treatments
for a wide variety of end-organ diseases once thought to be
incurable.
Conflict of Interest statement. None declared.
FUNDING
B.D.Y. is supported by National Institutes of Child Health and
Human Development (NICHD) HD04674 and the American
Skin Association.
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