title: Reduced FOXO1 expression accelerates skin wound healing and attenuates scarring.
abstract: The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1(+/-) mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a(-/-) mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1(+/-) mice, along with markedly altered extracellular signal-regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring.
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. Electronic address: ryoichi@nagasaki-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Mori
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; Department of Plastic and Reconstructive Surgery, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; Center for Medical Education and Research, Nagasaki Municipal Hospital, Nagasaki, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: de Kerckhove
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Department of Plastic and Reconstructive Surgery, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kashiyama
authors.affiliation: Department of Plastic and Reconstructive Surgery, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Sangeun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kawata
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Komatsu
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Seongjoon
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Forensic Pathology and Science, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ikematsu
authors.affiliation: Department of Plastic and Reconstructive Surgery, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Schools of Biochemistry and Physiology and Pharmacology, Faculty of Medical and Veterinary Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007627:Keloid / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing / Q000502:physiology*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse