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Am J Pathol. 2014 Sep;184(9):2465-79. doi: 10.1016/j.ajpath.2014.05.012. Epub 2014 Jul 8.

Reduced FOXO1 expression accelerates skin wound healing and attenuates scarring.

Author information

1
Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. Electronic address: ryoichi@nagasaki-u.ac.jp.
2
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.
3
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.
4
Department of Pathology, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
5
Department of Plastic and Reconstructive Surgery, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
6
Department of Forensic Pathology and Science, School of Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
7
Schools of Biochemistry and Physiology and Pharmacology, Faculty of Medical and Veterinary Sciences, University of Bristol, Bristol, United Kingdom.

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.

PMID:
25010393
PMCID:
PMC4188279
DOI:
10.1016/j.ajpath.2014.05.012
[Indexed for MEDLINE]
Free PMC Article

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