title: FOXO1 expression in keratinocytes promotes connective tissue healing.
abstract: Wound healing is complex and highly orchestrated. It is well appreciated that leukocytes, particularly macrophages, are essential for inducing the formation of new connective tissue, which requires the generation of signals that stimulate mesenchymal stem cells (MSC), myofibroblasts and fibroblasts. A key role for keratinocytes in this complex process has yet to be established. To this end, we investigated possible involvement of keratinocytes in connective tissue healing. By lineage-specific deletion of the forkhead box-O 1 (FOXO1) transcription factor, we demonstrate for the first time that keratinocytes regulate proliferation of fibroblasts and MSCs, formation of myofibroblasts and production of collagen matrix in wound healing. This stimulation is mediated by a FOXO1 induced TGFβ1/CTGF axis. The results provide direct evidence that epithelial cells play a key role in stimulating connective tissue healing through a FOXO1-dependent mechanism. Thus, FOXO1 and keratinocytes may be an important therapeutic target where healing is deficient or compromised by a fibrotic outcome.
authors.affiliation: Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China.|Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Chenying
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.|The fourth affiliated hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Ponugoti
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Alsadun
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Vafa
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003238:Connective Tissue / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014945:Wound Healing
chemical_list: D017077:Culture Media, Conditioned; D000071161:Forkhead Box Protein O1; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor