title: Keratinocyte-derived granulocyte-macrophage colony stimulating factor accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization.
abstract: Chronic, nonhealing wounds represent a major clinical challenge to practically all disciplines in modern medicine including dermatology, oncology, surgery, and hematology. In skin wounds, granulocyte-macrophage colony stimulating factor (GM-CSF) is secreted by keratinocytes shortly after injury and mediates epidermal cell proliferation in an autocrine manner. Many other cells involved in wound healing including macrophages, lymphocytes, fibroblasts, endothelial cells, and dendritic cells synthesize GM-CSF and/or are targets of this cytokine. Therefore, GM-CSF is a pleiotropic cytokine evoking complex processes during wound repair. Despite this complexity and the scarcity of mechanistic understanding GM-CSF has been employed in trials of clinical treatment of skin wounds with some success. In this study, we evaluated a transgenic mouse model in order to analyze the effects of an excess of keratinocyte-derived GM-CSF on excisional wound healing in the skin. Transgenic mice constitutively overexpressing GM-CSF in the basal layer of the epidermis displayed accelerated reepithelialization of full-thickness skin wounds. In the early stages of wound repair, transgenic mice exhibited significantly higher numbers of proliferating keratinocytes at the wound edges and increased formation of granulation tissue with enhanced neovascularization. As a potential mechanism of these beneficial changes, we identified the differential temporal regulation of cytokines such as transforming growth factor-beta, a known angiogenetic factor, interferon-gamma, a proinflammatory cytokine, and interleukin 6, an essential factor for reepithelialization, in transgenic mice versus controls. We propose that the beneficial effects observed in GM-CSF transgenics are due not only to direct GM-CSF action but in addition to indirect processes via the induction of secondary cytokines.
authors.affiliation: I. Medical Department, Johannes Gutenberg University, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mann
authors.forename: K
authors.initials: K
authors.lastname: Breuhahn
authors.forename: P
authors.initials: P
authors.lastname: Schirmacher
authors.forename: M
authors.initials: M
authors.lastname: Blessing
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006097:Granulation Tissue / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000098:blood supply / Q000166:cytology / Q000293:injuries; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D002273:Carcinogens; D016207:Cytokines; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate