Wnt signaling induces epithelial differentiation during cutaneous wound healing.
BACKGROUND
Cutaneous wound repair in adult mammals does not regenerate the original epithelial architecture and results in altered skin function. We propose that lack of regeneration may be due to the absence of appropriate molecular signals to promote regeneration. In this study, we investigated the regulation of Wnt signaling during cutaneous wound healing and the consequence of activating either the beta-catenin-dependent or beta-catenin-independent Wnt signaling on epidermal architecture during wound repair.


RESULTS
We determined that the expression of Wnt ligands that typically signal via the beta-catenin-independent pathway is up-regulated in the wound while the beta-catenin-dependent Wnt signaling is activated in the hair follicles adjacent to the wound edge. Ectopic activation of beta-catenin-dependent Wnt signaling with lithium chloride in the wound resulted in epithelial cysts and occasional rudimentary hair follicle structures within the epidermis. In contrast, forced expression of Wnt-5a in the deeper wound induced changes in the interfollicular epithelium mimicking regeneration, including formation of epithelia-lined cysts in the wound dermis, rudimentary hair follicles and sebaceous glands, without formation of tumors.


CONCLUSIONS
These findings suggest that adult interfollicular epithelium is capable of responding to Wnt morphogenic signals necessary for restoring epithelial tissue patterning in the skin during wound repair.
Fathke
Carrie
C
Department of Surgery, University of Washington School of Medicine, Seattle, WA 98195, USA. fathke@u.washington.edu
Wilson
Lynne
L
Shah
Kavita
K
Kim
Brian
B
Hocking
Anne
A
Moon
Randall
R
Isik
Frank
F
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004814:Epidermal Cyst / Q000209:etiology / Q000473:pathology; D004817:Epidermis / Q000293:injuries*; D004847:Epithelial Cells / Q000502:physiology*; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D018859:Hair Follicle / Q000378:metabolism; D015603:Keratinocytes / Q000473:pathology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012038:Regeneration / Q000187:drug effects; D012627:Sebaceous Glands / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C102068:Wnt10b protein, mouse; C508957:Wnt11 protein, mouse; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C438615:Wnt5a protein, mouse; C490508:Wnt7a protein, mouse; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride