miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1

Hasse Brønnum, Ditte C Andersen, Mikael Schneider, Maria B Sandberg, Tilde Eskildsen, Solveig B Nielsen, Raghu Kalluri, Søren P Sheikh

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.
OriginalsprogEngelsk
Artikelnummere56280
TidsskriftPLOS ONE
Vol/bind8
Udgave nummer2
Antal sider13
ISSN1932-6203
DOI
StatusUdgivet - 2013

Fingeraftryk

Cell death
MicroRNAs
Cell Death
apoptosis
microRNA
Fibroblasts
fibrosis
fibroblasts
heart
cells
Cadherins
Linings
Cell culture
phenotype
Muscle
cadherins
Actins
heart diseases
Cells
cell movement

Citer dette

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title = "miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1",
abstract = "The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.",
keywords = "Apoptosis Regulatory Proteins, Cluster Analysis, Epithelial-Mesenchymal Transition, Fibrosis, Gene Expression Profiling, Gene Expression Regulation, Humans, Membrane Proteins, MicroRNAs, Myocardium, Pericardium, Phenotype, Phosphoproteins, Primary Cell Culture, RNA-Binding Proteins",
author = "Hasse Br{\o}nnum and Andersen, {Ditte C} and Mikael Schneider and Sandberg, {Maria B} and Tilde Eskildsen and Nielsen, {Solveig B} and Raghu Kalluri and Sheikh, {S{\o}ren P}",
year = "2013",
doi = "10.1371/journal.pone.0056280",
language = "English",
volume = "8",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1. / Brønnum, Hasse; Andersen, Ditte C; Schneider, Mikael; Sandberg, Maria B; Eskildsen, Tilde; Nielsen, Solveig B; Kalluri, Raghu; Sheikh, Søren P.

I: PLOS ONE, Bind 8, Nr. 2, e56280, 2013.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1

AU - Brønnum, Hasse

AU - Andersen, Ditte C

AU - Schneider, Mikael

AU - Sandberg, Maria B

AU - Eskildsen, Tilde

AU - Nielsen, Solveig B

AU - Kalluri, Raghu

AU - Sheikh, Søren P

PY - 2013

Y1 - 2013

N2 - The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.

AB - The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.

KW - Apoptosis Regulatory Proteins

KW - Cluster Analysis

KW - Epithelial-Mesenchymal Transition

KW - Fibrosis

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Humans

KW - Membrane Proteins

KW - MicroRNAs

KW - Myocardium

KW - Pericardium

KW - Phenotype

KW - Phosphoproteins

KW - Primary Cell Culture

KW - RNA-Binding Proteins

U2 - 10.1371/journal.pone.0056280

DO - 10.1371/journal.pone.0056280

M3 - Journal article

VL - 8

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 2

M1 - e56280

ER -