Islet-1 is a dual regulator of fibrogenic epithelial-to-mesenchymal transition in epicardial mesothelial cells
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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.
Originalsprog | Engelsk |
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Tidsskrift | Experimental Cell Research |
Vol/bind | 319 |
Udgave nummer | 4 |
Sider (fra-til) | 424-435 |
Antal sider | 12 |
ISSN | 0014-4827 |
DOI | |
Status | Udgivet - 15 feb. 2013 |
Bibliografisk note
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 .
ID: 395075649