Re-epithelialization of cutaneous wounds in adult zebrafish combines mechanisms of wound closure in embryonic and adult mammals.
Re-epithelialization of cutaneous wounds in adult mammals takes days to complete and relies on numerous signalling cues and multiple overlapping cellular processes that take place both within the epidermis and in other participating tissues. Re-epithelialization of partial- or full-thickness skin wounds of adult zebrafish, however, is extremely rapid and largely independent of the other processes of wound healing. Live imaging after treatment with transgene-encoded or chemical inhibitors reveals that re-epithelializing keratinocytes repopulate wounds by TGF-β- and integrin-dependent lamellipodial crawling at the leading edges of the epidermal tongue. In addition, re-epithelialization requires long-range epithelial rearrangements, involving radial intercalations, flattening and directed elongation of cells - processes that are dependent on Rho kinase, JNK and, to some extent, planar cell polarity within the epidermis. These rearrangements lead to a massive recruitment of keratinocytes from the adjacent epidermis and make re-epithelialization independent of keratinocyte proliferation and the mitogenic effect of FGF signalling, which are only required after wound closure, allowing the epidermis outside the wound to re-establish its normal thickness. Together, these results demonstrate that the adult zebrafish is a valuable in vivo model for studying and visualizing the processes involved in cutaneous wound closure, facilitating the dissection of direct from indirect and motogenic from mitogenic effects of genes and molecules affecting wound re-epithelialization.
Institute of Developmental Biology, University of Cologne, Cologne D-50674, Germany rebecca.richardson@bristol.ac.uk mhammers@uni-koeln.de.
Rebecca
R
Richardson
Institute of Developmental Biology, University of Cologne, Cologne D-50674, Germany.
Manuel
M
Metzger
Institute of Developmental Biology, University of Cologne, Cologne D-50674, Germany Graduate School for Biological Sciences, University of Cologne, Cologne D-50674, Germany.
Philipp
P
Knyphausen
Institute of Developmental Biology, University of Cologne, Cologne D-50674, Germany.
Thomas
T
Ramezani
Georges-Koehler Laboratory, Max-Planck Institute of Immunobiology and Epigenetics, Freiburg D-79108, Germany.
Krasimir
K
Slanchev
Institute of Developmental Biology, University of Cologne, Cologne D-50674, Germany.
Christopher
C
Kraus
Cell Biology, Max-Planck Institute for Plant Breeding Research, Cologne D-50829, Germany.
Elmon
E
Schmelzer
Institute of Developmental Biology, University of Cologne, Cologne D-50674, Germany Center for Molecular Medicine Cologne, University of Cologne, Cologne D-50931, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne D-50931, Germany rebecca.richardson@bristol.ac.uk mhammers@uni-koeln.de.
Matthias
0000-0002-3709-8166
M
Hammerschmidt
D008841:Actin Cytoskeleton / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000502:physiology*; D004817:Epidermis / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000473:pathology; D008322:Mammals / Q000196:embryology*; D009024:Morphogenesis; D011554:Pseudopodia / Q000378:metabolism; D062326:Re-Epithelialization; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015027:Zebrafish / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism
D016023:Integrins; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases
Cell proliferation; FGF; Re-epithelialization; Skin; TGF-β; Wound healing