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21 WNT Epithelial 1510
21 WNT Epithelial 1510
REVIEW
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
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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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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.
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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.
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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
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
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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
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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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