title: miR-145 Is a Promising Therapeutic Target to Prevent Cornea Scarring.
abstract: Corneal scarring is an expected outcome of corneal injury or infection and is one of the major causes for visual loss. The formation of light-scattering myofibroblasts is thought to be the underlying cause of corneal haze formation. Recently, microRNA (miRNA) gene therapies have been proposed as novel approach for complex processes such as fibrosis and scarring. In this study, we focused on the role of miR-145 in corneal myofibroblast differentiation and function. Analysis of human corneal scar tissue and transforming growth factor (TGF)-β1-induced corneal myofibroblasts showed a 13- and 4-fold increase of miR-145, respectively, compared with healthy cornea and nonstimulated fibroblasts (p<0.01). Furthermore, myofibroblasts showed an increase in α-smooth muscle actin (α-SMA) expression and a decreased expression of Kruppel-like factor 4 (KLF4). These results indicated that TGF-β1 increases miR-145 expression, which indirectly induces α-SMA expression via downregulation of KLF4, a known negative regulator of α-SMA. Consistently, miR-145 silencing in corneal myofibroblasts using a specific antimiR resulted in increased KLF4 and strongly decreased α-SMA expression. In addition, miR-145 inhibition also significantly decreased myofibroblast contractility, migratory capacity, and TGF-β1 secretion, which are all thought to contribute to corneal scarring. Hence, miR-145 plays an important role in TGF-β1-stimulated corneal myofibroblast differentiation and activation, which can be reversed by miR-145 silencing. Therefore, we suggest miR-145 as a promising therapeutic target for miRNA-based gene therapy to prevent or treat visual loss caused by corneal fibrosis.
authors.affiliation: 1 Institute for Transfusion Medicine, Hannover Medical School , Hannover, Germany .
authors.forename: Dominica
authors.initials: D
authors.lastname: Ratuszny
authors.affiliation: 1 Institute for Transfusion Medicine, Hannover Medical School , Hannover, Germany .
authors.forename: Christiane
authors.initials: C
authors.lastname: Gras
authors.affiliation: 2 Clinic for Ophthalmology, Hannover Medical School , Hannover, Germany .
authors.forename: Anna
authors.initials: A
authors.lastname: Bajor
authors.affiliation: 1 Institute for Transfusion Medicine, Hannover Medical School , Hannover, Germany .
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Börger
authors.affiliation: 2 Clinic for Ophthalmology, Hannover Medical School , Hannover, Germany .
authors.forename: Amelie
authors.initials: A
authors.lastname: Pielen
authors.affiliation: 3 German Society for Tissue Transplantation , Hannover, Germany .
authors.forename: Martin
authors.initials: M
authors.lastname: Börgel
authors.affiliation: 2 Clinic for Ophthalmology, Hannover Medical School , Hannover, Germany .
authors.forename: Carsten
authors.initials: C
authors.lastname: Framme
authors.affiliation: 1 Institute for Transfusion Medicine, Hannover Medical School , Hannover, Germany .
authors.forename: Rainer
authors.initials: R
authors.lastname: Blasczyk
authors.affiliation: 1 Institute for Transfusion Medicine, Hannover Medical School , Hannover, Germany .
authors.forename: Constança
authors.initials: C
authors.lastname: Figueiredo
mesh_terms: D000199:Actins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics; D003315:Cornea / Q000254:growth & development / Q000473:pathology; D065306:Corneal Injuries / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005786:Gene Expression Regulation / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C541010:MIRN145 microRNA, human; D035683:MicroRNAs