title: Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-β-Slug signaling.
abstract: Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-β1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM(-/-)) wounds. Correspondingly, VIM(-/-) wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM(-/-) wounds. Vimentin reconstitution in VIM(-/-) fibroblasts restored both their proliferation and TGF-β1 production. Similarly, restoring paracrine TGF-β-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-β1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.
authors.affiliation: Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520, Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521, Turku, Finland;
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden; Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada V6Z 1Y6; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6Z 1Y6;
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520, Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521, Turku, Finland;
authors.forename: Ponnuswamy
authors.initials: P
authors.lastname: Mohanasundaram
authors.affiliation: Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520, Turku, Finland;
authors.forename: Michelle
authors.initials: M
authors.lastname: Lindström
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521, Turku, Finland; Department of Biochemistry and Food Chemistry, University of Turku, FI-20520, Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden;
authors.forename: Tor
authors.initials: T
authors.lastname: Ny
authors.affiliation: Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520, Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521, Turku, Finland; john.eriksson@abo.fi.
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014746:Vimentin / Q000172:deficiency / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics*
chemical_list: C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D016212:Transforming Growth Factor beta; D014746:Vimentin
keywords: epithelial–mesenchymal transition; fibroblast proliferation; keratinocyte migration; vimentin intermediate filaments; wound healing