Handchir Mikrochir Plast Chir 2020; 52(02): 151-158
DOI: 10.1055/a-1017-3600
Übersichtsarbeit

Wnt-Signalwege bei kutaner Wundheilung

Wnt signaling in cutaneous wound healing
K.S. Houschyar
1   Klinik für Dermatologie und Allergologie – Hautklinik, Universitätsklinik der RWTH Aachen
,
C. Tapking
2   Klinik für Hand-, Plastische- und Rekonstruktive Chirurgie, Schwerbrandverletztenzentrum, BG Unfallklinik Ludwigshafen, Universität Heidelberg
3   Department of Surgery, Shriners Hospitals for Children-Galveston, University of Texas Medical Branch, 815 Market Street, Galveston, TX, 77550, USA
,
B. Puladi
4   Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinik der RWTH Aachen
,
D. Popp
3   Department of Surgery, Shriners Hospitals for Children-Galveston, University of Texas Medical Branch, 815 Market Street, Galveston, TX, 77550, USA
5   Klinische Abteilung für Plastische, Ästhetische und Rekonstruktive Chirurgie, Universitätsklinik für Chirurgie, Medizinische Universität Graz, Österreich
,
D. Duscher
6   Klinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München
,
S. Rein
7   Klinik für Plastische und Handchirurgie mit Schwerbrandverletztenzentrum, Klinikum Sankt Georg, Delitzscher Straße 141, 04129 Leipzig
,
G. Reumuth
8   Abteilung für Plastische Chirurgie und Handchirurgie, Evangelische Elisabeth Klinik, Lehrkrankenhaus der Charité Berlin, Lützower Straße 24 – 26, 10785 Berlin
,
G. Grieb
9   Klinik für Plastische Chirurgie und Handchirurgie, Gemeinschaftskrankenhaus Havelhöhe, Lehrkrankenhaus der Charité Berlin, Kladower Damm 221, 14089 Berlin
,
L.K. Branski
3   Department of Surgery, Shriners Hospitals for Children-Galveston, University of Texas Medical Branch, 815 Market Street, Galveston, TX, 77550, USA
,
F. Siemers
10   Berufsgenossenschaftliches Klinikum Bergmannstrost Halle, Klinik für Plastische und Handchirurgie, Brandverletztenzentrum, Merseburger Str 165, 06112 Halle (Saale)
,
M. Lehnhardt
11   Klinik für Plastische Chirurgie und Schwerbrandverletzte, Handchirurgiezentrum, Operatives Referenzzentrum für Gliedmaßentumore, BG Universitätskliniken Bergmannsheil, Bochum
,
A.S Yazdi
1   Klinik für Dermatologie und Allergologie – Hautklinik, Universitätsklinik der RWTH Aachen
› Author Affiliations

Zusammenfassung

Die menschliche Haut ist eine effiziente Barriere, die den Organismus vor Noxen schützt. Wunden zerstören diese Barriere. Die Wundheilung ist eine in Phasen ablaufende physiologische Regeneration des zerstörten Gewebes, die im Idealfall zum Verschluss einer Wunde, insbesondere durch Neubildung von Bindegewebe und Kapillaren, führt. Der Wnt-Signalweg ist eine im gesamten Tierreich stark konservierte Signaltransduktionskaskade, durch die grundlegende zelluläre Interaktionen in multizellulären Organismen gesteuert werden. Entsprechend werden durch den Wnt-Signalweg viele Prozesse, z. B. die Balance zwischen Proliferation und Differenzierung oder die Apoptose, koordiniert. Die Wnt-Signalisierung wird durch eine Wunde aktiviert und nimmt an jeder nachfolgenden Phase des Heilungsprozesses teil, beginnend mit der Entzündungskontrolle und des programmierten Zelltods bis zur Mobilisation von Stammzellen innerhalb der Wunde. Die endogene Wnt-Signalverstärkung stellt einen attraktiven therapeutischen Ansatz dar, um die Wiederherstellung von Hautwunden zu unterstützen, da die komplexen Mechanismen des Wnt-Signalwegs im Laufe der Jahre zunehmend verstanden wurden. In dieser Übersichtsarbeit werden die aktuellen Daten zusammengefasst, um die Rolle der Wnt-Signalgebung beim Wundheilungsprozess der Haut zu verdeutlichen.

Abstract

Human skin is an efficient barrier that protects the organism from noxious substances. Wounds destroy this barrier. Wound healing is a phased physiological regeneration of the destroyed tissue that ideally leads to occlusion of a wound, in particular by regeneration of connective tissue and capillaries. The Wnt signaling pathway is a highly conserved signal transduction cascade across the animal kingdom that controls basic cellular interactions in multicellular organisms. Accordingly, through the Wnt signaling path many processes, e. g. as the balance between proliferation and differentiation or apoptosis, coordinated. Wnt signaling is activated by a wound and participates in each subsequent phase of the healing process, beginning with inflammatory control and programmed cell death, to the mobilization of stem cells within the wound. Endogenous Wnt signaling is an attractive therapeutic approach to assist in the repair of skin wounds, as the complex mechanisms of the Wnt signaling pathway have become increasingly understood over the years. This review summarizes current data to clarify the role of Wnt signaling in the wound healing process of the skin.



Publication History

Received: 13 May 2019

Accepted: 15 August 2019

Article published online:
13 November 2019

© Georg Thieme Verlag KG
Stuttgart · New York

 
  • Referenzen

  • 1 Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle) 2015; 4: 560-582
  • 2 Hodgson R. et al. Funding source and the quality of reports of chronic wounds trials: 2004 to 2011. Trials 2014; 15: 19
  • 3 Heyer K. et al. Epidemiology of chronic wounds in Germany: Analysis of statutory health insurance data. Wound Repair Regen 2016; 24: 434-442
  • 4 Augustin M. et al. Cost-of-illness of leg ulcers in the community. Int Wound J 2014; 11: 283-292
  • 5 Purwins S. et al. Cost-of-illness of chronic leg ulcers in Germany. Int Wound J 2010; 7: 97-102
  • 6 Yun MH. Changes in Regenerative Capacity through Lifespan. Int J Mol Sci 2015; 16: 25392-25432
  • 7 Leavitt T. et al. Scarless wound healing: finding the right cells and signals. Cell Tissue Res 2016; 365: 483-493
  • 8 Ogawa R. Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. Int J Mol Sci 2017; 18: 3
  • 9 Balana ME, Charreau HE, Leiros GJ. Epidermal stem cells and skin tissue engineering in hair follicle regeneration. World J Stem Cells 2015; 7: 711-727
  • 10 Shi J. et al. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases. J Immunol Res 2016; 2016: 9392132
  • 11 Augustin I. Wnt signaling in skin homeostasis and pathology. Augustin I 2015; 13: 302-306
  • 12 Fuchs E. Skin stem cells: rising to the surface. J Cell Biol 2008; 180: 273-284
  • 13 Lim X, Nusse R. Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb Perspect Biol 2013; 5: 2
  • 14 Lim CH. et al. Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing. Nat Commun 2018; 9: 4903
  • 15 Rognoni E. et al. Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing. Development 2016; 143: 2522-2535
  • 16 Houschyar KS. et al. Regulation of bone metabolism by the Wnt signaling pathway. Handchir Mikrochir Plast Chir 2018; 51 (04) 309-318
  • 17 Houschyar KS. et al. Role of Wnt signaling during inflammation and sepsis: A review of the literature. Int J Artif Organs 2018; 391398818762357
  • 18 Houschyar KS. et al. Wnt Pathway in Bone Repair and Regeneration – What Do We Know So Far. Front Cell Dev Biol 2018; 6: 170
  • 19 Gerlach JP. et al. Wnt signalling induces accumulation of phosphorylated beta-catenin in two distinct cytosolic complexes. Open Biol 2014; 4: 140120
  • 20 Shang S, Hua F, Hu ZW. The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017; 8: 33972-33989
  • 21 Sokol SY. Wnt signaling through T-cell factor phosphorylation. Cell Res 2011; 21: 1002-1012
  • 22 Carmon KS. et al. LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/beta-catenin signaling. Mol Cell Biol 2012; 32: 2054-2064
  • 23 Hrckulak D. et al. TCF/LEF Transcription Factors: An Update from the Internet Resources. Cancers (Basel) 2016; 8: 7
  • 24 Whyte JL. et al. Augmenting endogenous Wnt signaling improves skin wound healing. PLoS One 2013; 8: e76883
  • 25 Voloshanenko O. et al. Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nat Commun 2013; 4: 2610
  • 26 Hernandez-Maqueda JG. et al. Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines. PLoS One 2013; 8: e58540
  • 27 Teven CM. et al. Fibroblast growth factor (FGF) signaling in development and skeletal diseases. Genes Dis 2014; 1: 199-213
  • 28 Du X. et al. Role of FGFs/FGFRs in skeletal development and bone regeneration. J Cell Physiol 2012; 227: 3731-3743
  • 29 Gay D. et al. Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nat Med 2013; 19: 916-923
  • 30 Fathke C. et al. Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol 2006; 7: 4
  • 31 Phillips CJ. et al. Estimating the costs associated with the management of patients with chronic wounds using linked routine data. Int Wound J 2016; 13: 1193-1197
  • 32 Schmid A. et al. Modulation of Wnt signaling is essential for the differentiation of ciliated epithelial cells in human airways. FEBS Lett 2017; 591: 3493-3506
  • 33 Steele BM. et al. Canonical Wnt signaling negatively regulates platelet function. Proc Natl Acad Sci USA 2009; 106: 19836-19841
  • 34 Kumawat K, Gosens R. WNT-5A: signaling and functions in health and disease. Cell Mol Life Sci 2016; 73: 567-587
  • 35 Schaale K. et al. Wnt signaling in macrophages: augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur J Cell Biol 2011; 90: 553-559
  • 36 Brandenburg J, Reiling N. The Wnt Blows: On the Functional Role of Wnt Signaling in Mycobacterium tuberculosis Infection and Beyond. Front Immunol 2016; 7: 635
  • 37 Dissemond J, Goos M. Options for debridement in the therapy of chronic wounds. J Dtsch Dermatol Ges 2004; 2: 743-751
  • 38 Qing C. The molecular biology in wound healing & non-healing wound. Chin J Traumatol 2017; 20: 189-193
  • 39 Bielefeld KA. et al. Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing. J Biol Chem 2011; 286: 27687-27697
  • 40 Kim JH. et al. Roles of Wnt Target Genes in the Journey of Cancer Stem Cells. Int J Mol Sci 2017; 18: 8
  • 41 Shah A, Amini-Nik S. The Role of Phytochemicals in the Inflammatory Phase of Wound Healing. Int J Mol Sci 2017; 18: 5
  • 42 Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 2013; 70: 2059-2081
  • 43 Vallee A. et al. Interactions between TGF-beta1, canonical WNT/beta-catenin pathway and PPAR gamma in radiation-induced fibrosis. Oncotarget 2017; 8: 90579-90604
  • 44 Andrews JP. et al. Keloids: The paradigm of skin fibrosis – Pathomechanisms and treatment. Matrix Biol 2016; 51: 37-46
  • 45 Lam AP, Gottardi CJ. β-catenin signaling: a novel mediator of fibrosis and potential therapeutic target. Curr Opin Rheumatol 2011; 23: 562-567
  • 46 Rippa AL, Kalabusheva EP, Vorotelyak EA. Regeneration of Dermis: Scarring and Cells Involved. Cells 2019; 8: E607
  • 47 Darby IA. et al. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol 2014; 7: 301-311
  • 48 Serra MB. et al. From Inflammation to Current and Alternative Therapies Involved in Wound Healing. Int J Inflam 2017; 2017: 3406215
  • 49 Mostaço-Guidolin L, Rosin NL, Hackett TL. Imaging Collagen in Scar Tissue: Developments in Second Harmonic Generation Microscopy for Biomedical Applications. Int J Mol Sci 2017; 18: E1772
  • 50 Shin D, Minn KW. The effect of myofibroblast on contracture of hypertrophic scar. Plast Reconstr Surg 2004; 113: 633-640
  • 51 Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg 2010; 126: 1172-1180
  • 52 Mackool RJ, Gittes GK, Longaker MT. Scarless healing. The fetal wound. Clin Plast Surg 1998; 25: 357-365
  • 53 Moore AL. et al. Scarless wound healing: Transitioning from fetal research to regenerative healing. Wiley Interdiscip Rev Dev Biol 2018; 7: 2
  • 54 Burrington JD. Wound healing in the fetal lamb. Journal of Pediatric Surgery 1971; 6: 523-528
  • 55 Beanes SR. et al. Confocal microscopic analysis of scarless repair in the fetal rat: defining the transition. Plast Reconstr Surg 2002; 109: 160-170
  • 56 Basson MA. Signaling in cell differentiation and morphogenesis. Cold Spring Harb Perspect Biol 2012; 4: 6
  • 57 Longaker MT, Adzick NS. The biology of fetal wound healing: a review. Plast Reconstr Surg 1991; 87: 788-798
  • 58 Longaker MT. et al. Studies in fetal wound healing VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation. Journal of Pediatric Surgery 1990; 25: 63-69
  • 59 Longaker MT. et al. Studies in fetal wound healing. IV. Hyaluronic acid-stimulating activity distinguishes fetal wound fluid from adult wound fluid. Ann Surg 1989; 210: 667-672
  • 60 Yates CC, Hebda P, Wells A. Skin wound healing and scarring: fetal wounds and regenerative restitution. Birth Defects Res C Embryo Today 2012; 96: 325-333
  • 61 Takeo M, Lee W, Ito M. Wound healing and skin regeneration. Cold Spring Harb Perspect Med 2015; 5: a023267
  • 62 Plikus MV. et al. Epithelial stem cells and implications for wound repair. Semin Cell Dev Biol 2012; 23: 946-953