title: Aberrant Notch signalling contributes to hypertrophic scar formation by modulating the phenotype of keratinocytes.
abstract: Hypertrophic scar (HS) is characterized by fibroblast hyperproliferation and excessive matrix deposition. Aberrant keratinocyte differentiation and their abnormal cytokine secretion are said to contribute to HS by activating fibroblasts. However, the signalling pathway causing the aberrant keratinocytes in HS has remained unidentified thus far. Given that Notch signalling is crucial in initiating keratinocyte differentiation, we hypothesized that Notch signalling contributes to HS by modulating the phenotype of keratinocytes. We found that Notch1, Notch intracellular domain, Jagged1 and Hes-1 were overexpressed in the epidermis of patients with HS. Supernatants from recombinant-Jagged1-treated keratinocyte cultures could accelerate dermal fibroblast proliferation and collagen production. Furthermore, Jagged1 induced keratinocyte differentiation and upregulated the expression of fibrotic factors, including transforming growth factors β1 and β2 , insulin-like growth factor-1, connective tissue growth factor, vascular endothelial growth factor and epidermal growth factor, while DAPT (a Notch inhibitor) significantly suppressed these processes. In a rabbit ear model of HS, local application of DAPT downregulated the production of fibrotic factors in keratinocytes, together with ameliorated scar hyperplasia. Our findings suggest that Notch signalling contributes to HS by modulating keratinocyte phenotype. These results provide new insights into the pathogenesis of HS and indicate a potential therapeutic target.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Diao
authors.affiliation: Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Da-Lei
authors.initials: DL
authors.lastname: Wang
authors.affiliation: Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Chu
authors.affiliation: Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Shu-Zhong
authors.initials: SZ
authors.lastname: Guo
authors.affiliation: Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004151:Dipeptides / Q000494:pharmacology; D004431:Ear, External / Q000293:injuries; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D000072100:Jagged-1 Protein / Q000502:physiology; D015603:Keratinocytes / Q000473:pathology*; D010641:Phenotype; D000072417:Protein Domains; D011817:Rabbits; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1 / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human
keywords: fibroblasts; hypertrophic scar; keratinocytes