title: Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy.
abstract: Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is a major cause of corneal transplantation. It is characterized by abnormal deposition of extracellular matrix (ECM), such as corneal guttae, accompanied by a loss of endothelial cells. Although recent studies have revealed several genomic factors, the molecular pathophysiology of FECD has not yet been revealed. In this study, we establish a cellular in vitro model by using immortalized corneal endothelial cells obtained from late-onset FECD and control patients and examined the involvement of epithelial mesenchymal transition (EMT) on excessive ECM production. We demonstrate that the EMT-inducing genes ZEB1 and SNAI1 were highly expressed in corneal endothelial cells in FECD and were involved in excessive production of ECM proteins, such as type I collagen and fibronectin through the transforming growth factor (TGF)-β signaling pathway. Furthermore, we found that SB431542, a specific inhibitor of TGF-β type I ALK receptors, suppressed the expression of ZEB1 and Snail1 followed by reduced production of ECM. These findings suggest that increased expression levels of ZEB1 and Snail1 in FECD cells were responsible for an increased responsiveness to TGF-β present in the aqueous humor and excessive production of ECM. In addition, these results suggest that the regulation of EMT-related genes by blocking the TGF-β signaling pathway may be a feasible therapeutic strategy for FECD.
authors: Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.|Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Naoki
authors: N
authors: Okumura
authors: Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors: Ryuki
authors: R
authors: Minamiyama
authors: Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors: Leona Ty
authors: LT
authors: Ho
authors: Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors: EunDuck P
authors: EP
authors: Kay
authors: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Satoshi
authors: S
authors: Kawasaki
authors: Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Theofilos
authors: T
authors: Tourtas
authors: Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Ursula
authors: U
authors: Schlötzer-Schrehardt
authors: Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Friedrich E
authors: FE
authors: Kruse
authors: Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK.
authors: Robert D
authors: RD
authors: Young
authors: Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK.
authors: Andrew J
authors: AJ
authors: Quantock
authors: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Shigeru
authors: S
authors: Kinoshita
authors: Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors: Noriko
authors: N
authors: Koizumi
mesh_terms: D002461:Cell Line, Transformed; D005109:Extracellular Matrix / Q000378:metabolism*; D005642:Fuchs' Endothelial Dystrophy / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1