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MicroRNA expression in epicardial mesothelial cells undergoing Epithelial-to-Mesenchymal Transition

ABSTRACT: Cardiac fibrosis is a detrimental pathophysiological state involved in a number of cardiovascular diseases. Myofibroblasts mediate fibrosis by excessive remodeling of the extracellular matrix, which ultimately leads to tissue stiffness and impaired heart performance. Recently, it was shown that a substantial fraction of cardiac myofibroblasts may originate from the epicardium through Epithelial-to-Mesenchymal Transition (EMT). We have developed a cellular model of EMT in which adult murine epicardium-derived cells are differentiated into myofibroblast-like cells in the presence of Interleukin-1beta, Tumor Necrosis Factor-alpha, or Transforming Growth Factor-beta. Using this model of EMT, the microRNAome was assessed by microRNA (miRNA) arrays. Subsequently, expression levels of differentially expressed miRNAs were validated by qPCR. These miRNAs were targeted by transfecting epicardium-derived cells with anti- or pre-miRs prior to EMT initiation. The ability of the anti- or pre-miRs to inhibit EMT was assessed on a number of phenotypic markers. In this study we have identified a number of miRNAs that potentially play an intrinsic role in cardiac EMT. We speculate that by targeting those miRNA, the onset and long-term progression of cardiac fibrosis can be substantially reduced.

ORGANISM(S): Mus musculus Human gammaherpesvirus 8 JC polyomavirus Rattus norvegicus Betapolyomavirus macacae Murid gammaherpesvirus 4 Human immunodeficiency virus 1 Homo sapiens Human betaherpesvirus 5 Betapolyomavirus hominis Human alphaherpesvirus 1 human gammaherpesvirus 4 Murid betaherpesvirus 1

PROVIDER: GSE37627 | GEO | 2012/04/27

SECONDARY ACCESSION(S): PRJNA162385

REPOSITORIES: GEO

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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA

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MicroRNA expression in epicardial mesothelial cells undergoing Epithelial-to-Mesenchymal Transition

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