title: Islet-1 is a dual regulator of fibrogenic epithelial-to-mesenchymal transition in epicardial mesothelial cells.
abstract: Recent reports suggest that the adult epicardium is a source of cardiac progenitor cells having the ability to undergo epithelial-to-mesenchymal transition (EMT) and predominantly differentiate into myofibroblasts, thereby contributing to fibrosis of the stressed myocardium. Islet-1 (Isl1) is a widely applied marker of progenitor cells, including the epicardial mesothelial cells (EMCs). However, little is known of the general biological function of Islet-1, let alone its role in EMT of EMCs. Using rat-derived adult EMC cultures we therefore investigated the role of Isl1 expression in both non-stimulated EMCs and during TGF-β-induced EMT. We found that Isl1 had a dual role by promoting mesenchymal features in non-stimulated EMCs, while a loss of Isl1 associated with EMT acted as a negative modulator of EMT progression as assessed on phenotype. We furthermore found that the loss of Isl1 expression during EMT was, in addition to transcriptional regulation by β-catenin, mediated through direct targeting by microRNA-31 (miR-31). Through manipulations of miR-31 bioactivity in EMCs, we thus report that miR-31 is a negative modulator of cardiac fibrogenic EMT, primarily via targeting Isl1. Our data show that Isl1 is a key regulatory molecule in adult cardiac EMT.
authors.affiliation: Laboratory for Molecular and Cellular Cardiology, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Hasse
authors.initials: H
authors.lastname: Brønnum
authors.forename: Ditte C
authors.initials: DC
authors.lastname: Andersen
authors.forename: Mikael
authors.initials: M
authors.lastname: Schneider
authors.forename: Anne Yaël
authors.initials: AY
authors.lastname: Nossent
authors.forename: Solveig B
authors.initials: SB
authors.lastname: Nielsen
authors.forename: Søren P
authors.initials: SP
authors.lastname: Sheikh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099251:Myocardin
chemical_list: D060850:LIM-Homeodomain Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C570112:MIRN31 microRNA, rat; C063843:insulin gene enhancer binding protein Isl-1