title: Wound healing revised: a novel reepithelialization mechanism revealed by in vitro and in silico models.
abstract: Wound healing is a complex process in which a tissue's individual cells have to be orchestrated in an efficient and robust way. We integrated multiplex protein analysis, immunohistochemical analysis, and whole-slide imaging into a novel medium-throughput platform for quantitatively capturing proliferation, differentiation, and migration in large numbers of organotypic skin cultures comprising epidermis and dermis. Using fluorescent time-lag staining, we were able to infer source and final destination of keratinocytes in the healing epidermis. This resulted in a novel extending shield reepithelialization mechanism, which we confirmed by computational multicellular modeling and perturbation of tongue extension. This work provides a consistent experimental and theoretical model for epidermal wound closure in 3D, negating the previously proposed concepts of epidermal tongue extension and highlighting the so far underestimated role of the surrounding tissue. Based on our findings, epidermal wound closure is a process in which cell behavior is orchestrated by a higher level of tissue control that 2D monolayer assays are not able to capture.
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center, BIOQUANT, and 2 Department of Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Safferling
authors.forename: Thomas
authors.initials: T
authors.lastname: Sütterlin
authors.forename: Kathi
authors.initials: K
authors.lastname: Westphal
authors.forename: Claudia
authors.initials: C
authors.lastname: Ernst
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Merlin
authors.initials: M
authors.lastname: James
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
mesh_terms: D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D003198:Computer Simulation; D020405:Dermis / Q000473:pathology; D004817:Epidermis / Q000473:pathology; D004848:Epithelium / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D062793:Occludin / Q000378:metabolism; D019899:Paracrine Communication; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D014945:Wound Healing
chemical_list: D019394:Ki-67 Antigen; D062793:Occludin