Organogenesis, 11:95104, 2015

2015 Taylor & Francis Group, LLC

ISSN: 1547-6278 print / 1555-8592 online
DOI: 10.1080/15476278.2015.1086052

REVIEW

Wnt signaling induces epithelial differentiation during

cutaneous wound healing
Khosrow S Houschyar,1,2,* Arash Momeni,1 Malcolm N Pyles,1 Zeshaan N Maan,1
Alexander J Whittam,1 and Frank Siemers2
1

Division of Plastic and Reconstructive Surgery; Department of Surgery; Stanford School

of Medicine; Stanford, CA USA
2
Clinic for Plastic and Reconstructive Surgery; Bergmannstrost Halle, Germany

ABSTRACT. Cutaneous wound repair in adult mammals typically does not regenerate original
dermal architecture. Skin that has undergone repair following injury is not identical to intact
uninjured skin. This disparity may be caused by differences in the mechanisms that regulate postnatal
cutaneous wound repair compared to embryonic skin development and thus we seek a deeper
understanding of the role that Wnt signaling plays in the mechanisms of skin repair in both fetal and
adult wounds. The influence of secreted Wnt signaling proteins in tissue homeostasis has galvanized
efforts to identify small molecules that target Wnt-mediated cellular responses. Wnt signaling is
activated by wounding and participates in every subsequent stage of the healing process from the
control of inflammation and programmed cell death, to the mobilization of stem cell reservoirs within
the wound site. Endogenous Wnt signaling augmentation represents an attractive option to aid in the
restoration of cutaneous wounds, as the complex mechanisms of the Wnt pathway have been
increasingly investigated over the years. In this review, we summarize recent data elucidating the
roles that Wnt signaling plays in cutaneous wound healing process.
KEYWORDS. -catenin, regeneration, repair, stem cells, skin, Wnt

INTRODUCTION
Regeneration is the process of restoration,
renewal, and growth that fosters the ability

for genomes, cells, and organs to be resilient

to the natural fluctuations and events that
cause damage. It is important to distinguish
between repair, healing via formation of scar

*Correspondence to: Khosrow S Houschyar; Email: Khosrow.Houschyar@gmx.de

Submitted: April 3, 2015; Revised August 13, 2015; Accepted August 19, 2015.
95

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tissue, and regeneration, which is restoration

to the pre-injury state. Full-thickness skin
loss in adult mammals typically results in a
reparative rather than regenerative response,
leading to the formation of scar tissue.1
Deposition of a collagen-rich matrix in the
neo-dermis makes it prone to contracture,
decreases elasticity and tensile strength, and
promotes hypertrophic scar formation.2 Epithelialization without the development of an
epidermal appendage over a large surface
area leads to alopecia and thermal
imbalance.3
Processes involved in the healing of a skin
wound parallel embryonic skin development in
many ways. Both processes involve the differentiation, migration, proliferation, and apoptosis of various cell types to create the
multilayered tissue that constitutes the skin.
Many of the same key signaling pathways that
are activated during embryonic skin development are also activated during postnatal wound
healing; e.g. Wnt/-catenin, Notch, and Hedgehog pathways.4
Maintenance of epidermal homeostasis is
achieved by separate populations of stem
cells in the skin which includes stem cells
from the bulb region of the hair follicles,
the interfollicular epidermis, and the sebaceous glands.5 While both epidermal and
bulb stem cells have demonstrated the
potential to regenerate epidermis,6,7 an
effective cell-based approach utilizing these
population to promote scarless wound
healing remains elusive. There is increasing
evidence that Wnt proteins are necessary for
normal skin development.8,9,10 Recent data
demonstrate that the epidermis of wounded
adult mice can regenerate new hair follicles
during healing and that the origins of cells
that develop new hair follicles are Wntresponsive interfollicular stem cells, not
stem cells from the existing hair follicle
bulb.11
In the following sections we present a summation of data which provides strong evidence
that augmenting the endogenous Wnt pathway
improves cutaneous regeneration after injury
through activation of tissue-resident stem
cells.4,12-14

The three different Wnt signaling

pathways
The Wnt signaling pathway is an evolutionarily conserved pathway that regulates crucial
aspects of cell fate determination, cell polarity,
cell migration, neural patterning and organogenesis during embryonic development. Intracellular Wnt signaling diversifies into 3 main
branches: 1. the b-catenin pathway (canonical
Wnt pathway), which activates target genes in
the nucleus; 2. the planar cell polarity (PCP)
pathway, which involves jun N-terminal kinase
(JNK) and cytoskeletal rearrangements; and 3.
the Wnt/Ca2C pathway. In humans, there are
currently 19 different known Wnt proteins and
10 different Frizzled receptors. This review
will focus on canonical/-catenin dependent
Wnt signaling, which has been implicated in
tissue regeneration and repair.
The hallmark of canonical Wnt signaling is
the accumulation and translocation of the
adherens junction-associated protein, b-catenin, into the nucleus.15 Without Wnt signaling,
cytoplasmic b-catenin is degraded by a b-catenin destruction complex, which includes Axin,
adenomatosis polyposis coli (APC), glycogen
synthase kinase 3 (GSK3), protein phosphatase
2A (PP2A), and casein kinase 1a (CK1a).
Phosphorylation of b-catenin within this complex by Casein Kinase and GSK3 targets it for
ubiquitination and subsequent proteolytic
destruction by the proteosomal complex. Binding of Wnt to its receptor complex composed
of the Fz (frizzled) and the LRP5/6 triggers a
series of events that disrupt the APC/Axin/
GSK3 complex that is required for the targeted
destruction of b-catenin. The binding of Wnt
to the Fz/LRP5/6 complex induces the membrane translocation of a key negative regulator
of signaling. Binding of Axin has been proposed as the mechanism for reduction of the
inhibitory activity of Axin on canonical Wnt
signaling.53 This leads to activation of the
phosphoprotein Dishevelled (Dsh), which
inhibits the activity of the GSK3 enzyme, preventing the degradation of b-catenin, allowing
consequent stabilization and accumulation in
the cytoplasm. Stabilized b-catenin translocates into the nucleus, exerting its effect on

Wnt SIGNALING PATHWAY

gene transcription by functioning as a transcriptional co-activator. A large number of

binding partners for b-catenin in the nucleus
has been uncovered and perhaps the best characterized are the members of the LEF/TCF
DNA-binding transcription factors. This complex binds to the promoter of target genes
(e.g., Cyclin D1, MT1-MMP (membrane-type
1-matrix metalloproteinase), MMP-7 or Dkk-1
(Dickkopf) and these genes are required for
organizer formation during embryogenesis.16
(Fig. 1).

The role of Wnt signaling in tissue

regeneration/repair
The Wnt pathway regulates cell proliferation
in the adult epidermis, which directly impacts
the rate and extent of skin wound healing.
Using the Axin2-Cre lineage reporter mice, one
study was able to show that the majority of the

97

basal epidermal layer requires Wnt/b-catenin

signaling to proliferate and these same cells
contribute robustly to wound healing, with no
requirement for a quiescent stem cell subpopulation.13 Wnt proteins also serve as niche signals for at least 2 types of skin stem cells that
contribute to skin wound healing; those in the
bulge region of the hair follicle,(17) and those
in the basal layer of the interfollicular epidermis.18 Several lines of other evidence indirectly
supports a role for Wnt signaling in cutaneous
repair.12,19,20
The concept that wound healing recapitulates embryonic development is illustrated by
the interesting finding that the source of new
follicles is not cells within the hair follicle stem
cell niche.21 Recent studies showed that fibroblast growth factor (FGF) signaling plays multiple inductive roles during development of
vertebrates.22 FGF-9 modulates hair follicle
regeneration after skin injury in adult mice and
FGF-9 triggers Wnt expression with subsequent

FIGURE 1. Canonical Wnt signaling pathway. In the absence of signal, action of the destruction
complex (CKIa, GSK-3b, APC, Axin) creates a hyperphosphorylated b-catenin, which is a target
for ubiqitination and degradation by the proteosome. Binding of Wnt ligand to a Frizzled/LRP-5/6
receptor complex leads to stabilization of hypophosphorylated b-catenin, which interacts with TCF/
LEF proteins in the nucleus to activate transcription. In a canonical pathway, CKIa, GSK-3b, APC,
and Axin act as negative regulators and all other components act positively. Abbreviations: APC D
adenomatous polyposis coli, CK D casein kinase, GSK D glycogen synthase kinase, Fzd D Frizzled-Rezeptor, LRP D low-density-lipoprotein receptor related protein, Tcf/Lef D T cell-specific transcription factor/lymphoid enhancer-binding factor.

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Houschyar et al.

Wnt activation in wound fibroblasts.23 Through

a unique feedback mechanism, activated fibroblasts then express FGF-9, thus amplifying
Wnt activity throughout the wound dermis during a crucial phase of skin regeneration
(Fig. 2). Skin wounds express various Wnt proteins during the early phases of healing, with
transcripts of Wnts 1, 3, 4, 5a, and 10b being
present in murine full-thickness cutaneous
wounds up to 7 d after injury.24 In the epithelium, Wnt 10b protein can be detected in
migrating epithelial cells up to 3 d after wounding, while Wnt 4, 5a, and 10b localize to hair
follicles.25 Wnt 2a and 4 are expressed in the
dermis, although reports vary with respect to
the time-course of their expression (range: 30 h
7 d after wounding). It appears that Wnt

signaling, through its ability to activate stem

cells with induction of their self-renewal and
proliferation, serves as a positive stimulus for
wound repair.

STAGES OF SKIN REGENERATION

Hemostasis and inflammation are
dependent on Wnt signaling
Wound healing is classically described as a
process involving 3 overlapping phases (Fig. 3).
The resolution of injury begins with hemostasis.
Vasoconstriction and clot formation lead to cessation of bleeding. Hemostasis is achieved
through the activation of platelets and the

FIGURE 2. Wnt signaling maintains the hair-inducing activity in skin repair. Fibroblast growth factor
(Fgf) 9 is a secreted signaling molecule that is expressed in epithelium. Mesenchymal Fgf signaling
interacts with b-catenin-mediated Wnt signaling in a feed-forward loop that functions to sustain
mesenchymal Fgf responsiveness and mesenchymal Wnt/b-catenin signaling. Wnt2a is a canonical Wnt ligand that activates mesenchymal Wnt/b-catenin signaling, whereas Fgf9 is the only
known ligand that signals to mesenchymal Fgf receptors (FGFRs). Mesothelial Fgf9 and mesenchymal Wnt2a are principally responsible for maintaining mesenchymal Fgf-Wnt/b-catenin signaling, whereas epithelial Fgf9 primarily affects epithelial branching. In summary, Fgf signaling is
primarily responsible for regulating mesenchymal proliferation, whereas b-catenin signaling is a
required permissive factor for mesenchymal Fgf signaling. Abbreviations: Fgf D Fibroblast growth
factor.

Wnt SIGNALING PATHWAY

99

FIGURE 3. There are 3 classic stages of wound repair: inflammation (a), proliferation (b) and
remodeling (c). (a) Inflammation. This stage lasts until about 48 h after injury and depicted is a skin
wound at about 2448 h after injury. The wound is characterized by a hypoxic (ischemic) environment in which a fibrin clot has formed and platelets aggregate. Platelets adhere to the injured endothelium and release chemokines, thereby attracting the cellular components of the inflammatory
stage. The inflammatory stage of wound healing is characterized by the presence of neutrophils,
macrophages, lymphocytes and local Wnt signaling begins to increase. The inflammatory cells
then serve to release proinflammatory cytokines, growth factors and vascular endothelial growth
factor, ingest foreign materials, increase vascular permeability, and promote fibroblast activity. (b)
Proliferation. This stage occurs about 210 d after injury and depicted is a skin wound at about 5
10 d after injury. This stage includes an increased local Wnt response, capillary growth and granulation tissue formation occur and an eschar has formed on the surface of the wound. (c) Remodeling. This stage lasts for a year or longer and depicted is a skin wound about 112 months after
repair. The final stage of wound healing is a long process of tissue remodeling and increasing
wound strength. During this stage, type I collagen synthesis and turnover continues, and fibroblasts
differentiate into myofibroblasts, allowing further wound contraction.

coagulation cascade.26 Recent data suggests that

Wnt signaling is essential for development of
megakaryocytes and for stimulating proplatelet
function in vitro.27 Interestingly, canonical Wnt
has been shown to inhibit platelet aggregation.28
whereas non-Canonical Wnt-5A, stimulates
platelet aggregation.29

Following hemostasis is the start of the

inflammatory phase which is characterized by
the presence of erythema (rubor), warmth
(calor), edema (tumor), and pain (dolor).30 At a
cellular level, inflammation involves blood vessel dilation, increased vascular permeability, and
leukocyte recruitment to the site of injury. Two

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Houschyar et al.

leukocyte populations sequentially dominate the

inflammatory events of wound healing: neutrophils and macrophages.31 Both provide the critical function of wound debridement, whereas the
latter population is critical in orchestrating the
subsequent steps in wound healing. More
recently, Wnt signaling has been shown to be
involved in the regulation of inflammatory processes. Wnt5a is induced in human macrophages
in response to mycobacteria and conserved bacterial structures, contributing to the regulation of
pro-inflammatory cytokines via its receptor Frizzled (Fzd) 5.32 Wnt5a is also induced in other
infectious and inflammatory diseases such as
tuberculosis, sepsis, psoriasis, rheumatoid arthritis and atherosclerosis.32 -Catenin-dependent
Wnt signaling, therefore, robustly enhances the
inflammatory response.33

Proliferation
Wound debridement is critical in enhancing
the inflammatory process by reducing wound
bacterial counts and removing necrotic tissue
which impedes the healing process.34 Once
debrided, the wound enters the proliferative
phase which takes place around post-injury days
4 through 12. During this time period, fibroblasts, smooth muscle cells, and endothelial
cells infiltrate the wound as epithelial cells begin
to cover the site of injury.35 In concert, these
cells reestablish tissue continuity through matrix
deposition, angiogenesis, and epithelialization.
-Catenin is an important regulator of fibroblast
behavior during the proliferative phase of dermal wound repair.36 -Catenin protein levels
and transcriptional activity are elevated in dermal fibroblasts during the proliferative phase of
healing in murine cutaneous wounds and return
to baseline during the remodeling phase. Human
wounds similarly show increased expression of
-catenin and its target genes, such as fibronectin and MMP7, during the proliferative phase.37
While increased -catenin activity during the
proliferative phase is crucial for successful
wound repair, prolonged or aberrant -catenin
activity beyond the normal parameters of healing contributes to excessive fibrosis and scar
formation. Indeed, human hypertrophic scars
and keloids exhibit elevated -catenin levels.38

Interestingly, while Wnt ligands may participate

in stimulating dermal -catenin during wound
repair, Wnt signaling is not crucial for maintaining elevated -catenin levels during the proliferative phase of cutaneous healing. This has been
demonstrated in mice treated with an adenovirus
expressing the Wnt signaling inhibitor Dickkopf
(DKK1, which binds LRP6/Arrow), without a
significant decline in -catenin protein levels
during the proliferative phase of skin wound
healing, in contrast to the situation in bone
repair.39 This suggests that other factors play a
role in regulating -catenin levels during the
proliferative phase of healing. Indeed, -catenin
levels in fibroblasts can be stimulated by growth
factors, such as TGF-1, which are released during the early stages of wound repair. Furthermore, -catenin activity in dermal fibroblasts is
regulated by extracellular matrix (ECM) components, such as fibronectin, which activates
-catenin through a GSK3-dependent, 1
integrin mediated pathway.40 Hypertrophic
scars and keloids represent a dysregulated
response to cutaneous wounding, resulting in an
excessive deposition of ECM, especially collagen. TGF-b is believed to be responsible for
excessive ECM deposition in hypertrophic
scars, keloids and other fibrotic conditions.41
Since b-catenin is known to accumulate during
fibroproliferation,42 we speculate that it could
play a role in the mechanisms that lead to hypertrophic/keloid scarring. -Catenin and Wnt signaling are intrinsically involved in the
formation of the dermis and of epidermal structures, both during wound repair and during skin
development. It will be interesting to elucidate
whether non-Wnt activators of -catenin, such
as ECM proteins and growth factors, modulate
-catenin during skin development as they do
during the response to injury.

Wound remodeling
In the skin epithelium, remodeling consists
of deposition of matrix and subsequent changes
in its organization and composition over time.
This final phase of wound healing occurs
throughout the entire wound repair process and
continues for up to 1 y after injury.43 Fibrin
clot formed in the early inflammatory phase is

Wnt SIGNALING PATHWAY

replaced by granulation tissue that is rich in

type III collagen and blood vessels during the
proliferative phase and subsequently replaced
by a collagenous scar predominantly of type I
collagen.44 Wnt is responsible for the differentiation of myofibroblasts of mesenchymal stem
cell;45 myofibroblasts cause wound contracture,
decreasing the surface of the developing scar.46
Wnt has also been shown as critical in the process of angiogenesis and endogenous enhancement of Wnt can correct vascular defects.47 As
angiogenic processes diminish, wound blood
flow declines, and acute wound metabolic
activity slows, eventually stopping.

DIFFERENCES BETWEEN FETAL

WOUND HEALING AND ADULT
WOUND HEALING
Although it has been almost 3 decades since
the discovery of scarless fetal healing, the key
to scarless repair remains elusive.48 Investigators have now begun applying more comprehensive transcriptomic techniques to the study
of scarless wound healing. In particular, there
has been a focus on the time during fetal gestation when regenerative healing changes to adult
wound healing with scar formation in order to
understand
the
phenomena
occurring

101

immediately before and after this transition. In

rats, wounds made on the 16th day of gestation
(gestation period: 21 days) histologically
regenerate, but wounds made on the 18th day
of gestation are associated with scarring.49,50 In
wounds made during the regenerative phase,
the skin, including appendages and panniculus
carnosus muscle, is completely regenerated,
whereas the scarring reparative response does
not include regeneration of the hair bulb and
skin texture.51 The major objective of skin
wounding research is restoration of the extracellular matrix architecture, and a subsequent
return of strength and function to the injured
skin. It therefore must overcome the fibrotic
nature of post-natal wound healing. It is clear
from studies conducted in mammals that normal skin development absolutely depends on a
tight regulation of the activities of secreted signaling molecules that display potent organizing
properties in the embryo.52 These signaling
molecules include members of the Hedgehog
(Hh), transforming growth factor-b (TGF-b),
and Wnt families of secreted factors (Table 1).
Based on the studies mentioned above, it is
clear that fetal wound healing eventually
changes over to adult wound healing. Here, we
focus on a particular mode of regulation of the
activity of Wnt proteins to aid in the regeneration of skin architecture after wounding.

Table 1. Summary of developmental signaling pathways in mammalian skin development and

repair
Signaling pathway

Skin section

Skin development

Skin repair

Wnt

Wnt

Development and
morphogenesis of hair follicles
Development of
the dermis

Regeneration of hair
follicles in large wounds
Reconstitution of the dermis:
fibroblast numbers and behavior,
matrix production
Present in regenerated hair follicles

Dermis

Sonic hedgehog

Epidermis
Dermis

TGF-b

Epidermis
Dermis

Notch

Epidermis
Dermis

Development and
morphogenesis of hair follicles
Role previously unknown
No significant role in hair
follicle development
Role previously unknown
Expressed in developing dermis
Epidermal differentiation
Role previously unknown

Involved in dermal reconstitution: effects

on matrix, cellularity and vascularity
Inhibitory role in re-epithelialization
Reconstitution of the dermis: fibroblast
proliferation and behavior, myofibroblast
formation, matrix production, wound contraction
Role previously unknown
Involved in dermal reconstitution:effects
on macrophage behavior,angiogenesis

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Houschyar et al.

CONCLUSIONS AND CLINICAL

ASPECTS OF SKIN REGENERATION/
REPAIR
Our understanding of skin wound healing
mechanisms has progressed considerably in
recent years. The wound epithelium in adult
mammals is just as capable of responding to
morphogenic signals from the dermis as it
does in the embryo during hair placode formation. Adult stem cells have tremendous
therapeutic potential, and the skin epithelium
represents an enormous source of accessible
stem cells that might be a starting point for
generating cells to replace diseased tissue.
Skin stem cells have already been used to
replace skin lost to burns; whether it will be
possible to use skin stem cell plasticity to
engineer treatments for other disorders
remains to be determined. Although increasing evidence supports a role for Wnt signaling in skin epithelial stem cell maintenance
and/or determination, deregulated Wnt signaling activation has long been implicated in
human cancers. Wnt signaling is essential at
multiple steps during the complex organogenesis of the skin and its appendages. It is
required to induce the formation of the dorsal dermis and regulates the size of the different skin appendage tracts. Later, Wnt
signaling is required for the very early stages
of skin appendage formation. Skin appendage distribution and pigmentation are regulated, in part by Wnt signaling. Disruption
of the pathway can lead to the formation of
skin appendage tumors. Any strategy that
attempts to target the Wnt pathway to augment tissue regeneration will have to take
into consideration the need to selectively and
locally activate signaling in the tissue or
area of interest, while simultaneously
restricting Wnt signaling in other parts of
the body. The intricate and dynamic nature
of the wound environment suggests that successful therapies for treating wound healing
disorders will not rely upon a single allencompassing agent, but will likely require a
multitude of factors for a finely tuned attenuation of endogenous Wnt signaling during

the wound healing process. Identifying the

relationships between developmental signaling pathways in adult wound repair and fetal
skin development and/or regeneration will
certainly propel the research community
closer to this goal, and is a fruitful area of
future investigation.

DISCLOSURE OF POTENTIAL
CONFLICTS OF INTEREST
No potential conflicts of interest were
disclosed.

FUNDING
Funding for this research have been provided
by the Hagey Family Endowed Found in Stem
Cell Research and Regenerative Medicine, The
Oak Foundation, and the National Library of
Medicine (#LM0077033 to MJ).
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