TY - JOUR

T1 - Islet-1 is a dual regulator of fibrogenic epithelial-to-mesenchymal transition in epicardial mesothelial cells

AU - Brønnum, Hasse

AU - Andersen, Ditte C.

AU - Schneider, Mikael

AU - Yaël Nossent, Anne

AU - Nielsen, Solveig B.

AU - Sheikh, Søren P.

N1 - Funding Information: This work was supported by the Odense University Hospital , The John and Birthe Meyer Foundation , The Danish Heart Association , The Augustinus Foundation , The King Chr. X Foundation , The Director Jacob Madsen and Wife Olga Madsen's Foundation , The Mogens Rendal Foundation , The Fuhrmann Foundation , The Carpenter Alfred Andersen and Wife's Foundation , The Danish National Research Council ( #09-073648 ) and The Danish Ministry of Science, Technology and Innovation .

PY - 2013/2/15

Y1 - 2013/2/15

N2 - 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.

AB - 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.

KW - Epicardium

KW - Epithelial-to-mesenchymal transition

KW - Fibrosis

KW - Islet-1

KW - MicroRNA-31

UR - http://www.scopus.com/inward/record.url?scp=84875526984&partnerID=8YFLogxK

U2 - 10.1016/j.yexcr.2012.12.019

DO - 10.1016/j.yexcr.2012.12.019

M3 - Journal article

C2 - 23270756

AN - SCOPUS:84875526984

VL - 319

SP - 424

EP - 435

JO - Experimental Cell Research

JF - Experimental Cell Research

SN - 0014-4827

IS - 4

ER -