Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy

Sommariva, Elena; Brambilla, Silvia; Carbucicchio, Corrado; Gambini, Elisa; Meraviglia, Viviana; Russo, Antonio Dello; Farina, Floriana Maria; Casella, Michela; Catto, Valentina; Pontone, Gianluca; Chiesa, Mattia; Stadiotti, Ilaria; Cogliati, Elisa; Paolin, Adolfo; Alami, Najwa Ouali; Preziuso, Carmela; d’Amati, Giulia; Colombo, Gualtiero I.; Rossini, Alessandra; Capogrossi, Maurizio C.; Tondo, Claudio; Pompilio, Giulio

doi:10.1093/eurheartj/ehv579

Cited by 86 publications

(163 citation statements)

References 47 publications

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“…Moreover, adult cardiac myocytes are terminally differentiates cells with limited, if any, capacity for fate switch. In contrast, MPCs have the potential to differentiate to different lineages and been identified as a cell source of adipocytes in AC 36, 44 . Nevertheless, despite demonstration of the role of MiR-184 in regulating cell fate in two different cell types, the findings merit testing in in vivo models, in order to determine contributions of miR-184 to adipogenesis in AC.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro

Gurha

Chen

Lombardi

et al. 2016

Circulation Research

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Rationale PKP2, encoding plakophilin 2 (PKP2), is the most common causal gene for arrhythmogenic cardiomyopathy (AC). Objective To characterize miRNAs expression profile in PKP2-deficient cells Methods and Results Control and PKP2-knock down HL-1 (HL-1Pkp2-shRNA) cells were screened for 750 miRNAs using low-density microfluidic panels. Fifty-nine miRNAs were differentially expressed. MiR-184 was the most down-regulated miRNA. Expression of miR-184 in the heart and cardiac myocyte was developmentally downregulated and was low in mature myocytes. MicroRNA-184 was predominantly expressed in cardiac mesenchymal progenitor cells (MPCs). Knock down of Pkp2 in cardiac MPCs also reduced miR-184 levels. Expression of miR-184 was transcriptionally regulated by the E2F1 pathway, which was suppressed in PKP2-deficient cells. Activation of E2F1, upon over-expression of its activator CCND1 or knock down of its inhibitor RB1, partially rescued miR-184 levels. In addition, DNMT1 was recruited to the promoter region of miR-184 and the CpG sites at the upstream region of miR-184 were hypermethylated. Treatment with 5-aza-2’-deoxycytidine, a demethylation agent, and knock down of DNMT1 partially rescued miR-184 level. Pathway analysis of paired miR-184:mRNA targets identified cell proliferation, differentiation, and death as the main affected biological processes. Knock down of miR-184 in HL-1 cells and MPCs induced and conversely, its over-expression attenuated adipogenesis. Conclusions PKP2 deficiency leads to suppression of the E2F1 pathway and hypermethylation of the CpG sites at miR-184 promoter, resulting in downregulation of miR-184 levels. Suppression of miR-184 enhances and its activation attenuates adipogenesis in vitro. Thus, miR-184 contributes to the pathogenesis of adipogenesis in PKP2-deficient cells.

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Section: Discussionmentioning

confidence: 99%

Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro

Gurha

Chen

Lombardi

et al. 2016

Circulation Research

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“…In summary, adult cCFU-F are likely to represent one type of cardiac lineage progenitor, possibly maintaining the stromal, matrix, vascular and adipocyte compartments of the heart during homeostasis, and contributing to vascular cells and myofiboblasts during heart repair. cCFU-F also probably contribute to fibrosis and fibro-fatty infiltration that accompanies certain cardiac pathologies (Sommariva et al, 2015). Cardiac stromal cells probably also act as sentinels of cardiac stress and autocrine function, and mediate local cellular dialogs with other cardiac-resident cells, including cardiomyocytes and immune cells, through paracrine mechanisms (Amoah et al, 2015;Ieda et al, 2009).…”

Section: Cre−ert2mentioning

confidence: 99%

Developmental origin and lineage plasticity of endogenous cardiac stem cells

et al. 2016

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Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT + , PDGFRα + , ISL1 + and SCA1 + cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair.

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“…Thus, cells other than cardiomyocytes must be involved in the abnormal adipogenesis and fibrosis which is an essential feature of AC phenotype [100]. A role of cardiac mesenchymal stromal cells as a source of adipocytes in AC has been recently suggested [101]. …”

Section: Abnormal Intercellular Junction Proteins and Intracellular Smentioning

confidence: 99%

Arrhythmogenic Cardiomyopathy

Pilichou¹,

Basso²,

Corrado³

et al. 2018

Diagnosis and Management of Adult Congenital Heart Disease

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Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy

Cited by 86 publications

References 47 publications

Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro

Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro

Developmental origin and lineage plasticity of endogenous cardiac stem cells

Arrhythmogenic Cardiomyopathy

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