Interacting Resident Epicardium-Derived Fibroblasts and Recruited Bone Marrow Cells Form Myocardial Infarction Scar

Ruiz‐Villalba, Adrián; Simón, Ana María; Pogontke, Cristina; Castillo, María Isabel Archilla; Abizanda, Gloria; Pelacho, Beatriz; Sanchez-Dominguez, Rebeca; Segovia, José C.; Prósper, Felipe; Pérez‐Pomares, José M.

doi:10.1016/j.jacc.2015.03.520

Cited by 137 publications

(146 citation statements)

References 24 publications

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“…This conclusion agrees with the work of Entman and colleagues 6,9,68–70 showing that during ischemic cardiomyopathy and heart failure, BM monocytes recruited into the tissue differentiate into CD45+ mesenchymal cells and contribute to fibrosis and adverse remodeling. This conclusion also agrees with studies 10,71–73 demonstrating a contribution of hematopoietic cells to mesenchymal cell populations in fibrotic tissue using chimeric mouse models wherein genetically-tagged (eg, EGFP) cells are used to reconstitute the BM of irradiated mice. This conclusion is challenged by investigators who have depended on Cre drivers for lineage specificity and on the failure to stain fibrotic tissues for CD45, 2,3,74 a difficult protein to detect without proper fixation.…”

Section: Discussionsupporting

confidence: 89%

Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide

Jenkins¹,

Reese

Chinnakkannu³

et al. 2017

Laboratory Investigation

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Chronic ventricular pressure overload (PO) results in congestive heart failure (CHF) in which myocardial fibrosis develops in concert with ventricular dysfunction. Caveolin-1 is important in fibrosis in various tissues due to its decreased expression in fibroblasts and monocytes. The profibrotic effects of low caveolin-1 can be blocked with the caveolin-1 scaffolding domain peptide (CSD, a caveolin-1 surrogate) using both mouse models and human cells. We have studied the beneficial effects of CSD on mice in which PO was induced by trans-aortic constriction (TAC). Beneficial effects observed in TAC mice receiving CSD injections daily included: improved ventricular function (increased ejection fraction, stroke volume, and cardiac output; reduced wall thickness); decreased collagen I, collagen chaperone HSP47, fibronectin, and CTGF levels; decreased activation of non-receptor tyrosine kinases Pyk2 and Src; and decreased activation of eNOS. To determine the source of cells that contribute to fibrosis in CHF, flow cytometric studies were performed that suggested that myofibroblasts in the heart are in large part bone marrow-derived. Two CD45+ cell populations were observed. One (Zone 1) contained CD45+/HSP47 −/macrophage marker+ cells (macrophages). The second (Zone 2) contained CD45moderate/HSP47+/macrophage marker − cells often defined as fibrocytes. TAC increased the number of cells in Zones 1 and 2 and the level of HSP47 in Zone 2. These studies are a first step in elucidating the mechanism of action of CSD in heart fibrosis and promoting the development of CSD as a novel treatment to reduce fibrosis and improve ventricular function in CHF patients.

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Section: Discussionsupporting

confidence: 89%

Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide

Jenkins¹,

Reese

Chinnakkannu³

et al. 2017

Laboratory Investigation

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“…Ischemia-associated FBs have a critical influence on myocardial remodeling progression and fibrosis. [1][2][3] Myocardial remodeling is the product of interactions between FBs and adjacent cells, such as CMs, and blood vascular endothelial cells (ECs), although the exact mechanisms remain poorly understood. 4,5 Pleiotropic effects of cardiac FBs are mediated through differentiation to a myofibroblast phenotype and secretion of pro-inflammatory cytokines (eg, IL-6, TGF β, TNFα, and IL-1).…”

mentioning

confidence: 99%

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

Wang

Zhao

Pan

et al. 2016

Laboratory Investigation

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Interlukin-6 (IL-6) is a multifunctional cytokine produced by several cell types that has a role in fibrosis. Fibroblasts (FBs) maintain this underlying pathogenic change through regulation of IL-6 production; however, its potential functional role in regulating surrounding cellular structural changes during ischemic myocardial remodeling remains unexplored. Here, we generated FBs, cardiomyocytes (CMs), and blood vascular endothelial cells (ECs) from the ventricles of neonatal rats. IL-6 was then overexpressed in FBs and the cells were treated with IL-6 receptor inhibitor (IL6RI), TGF-β1 receptor inhibitor (TβRI), or MMP2/MMP9 inhibitor (MMPI) using monoculture or coculture models under hypoxic conditions. The results indicate that overexpression of IL-6 is sufficient to induce myofibroblastic proliferation, differentiation, and fibrosis, probably via increased TGF-β1-mediated MMP2/MMP3 signaling. The use of IL6RI, TβRI, or MMPI diminished these effects. In addition, IL-6 activated the apoptosis-associated factors Caspase3 and Smad3, and decreased the expression of anti-apoptotic factor Bcl2, resulting in apoptosis of CMs under hypoxic coculture: IL6RI or TβRI inhibited these effects. Unexpectedly, IL-6-overexpressing FBs significantly increased the angiogenesis of ECs, which involved significant increases in the expression of proangiogenic growth factors. Treatment of FBs with IL6RI or TβRI in coculture with ECs reduced the levels of secreted proangiogenic growth factors, and the angiogenesis of ECs was significantly downregulated. Thus, IL-6 functions in ischemic myocardial remodeling through multifunctional reprogramming of hypoxia-associated FBs towards fibrosis via upregulation of the TGF-β1 signaling pathway.

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“…Most infarct myofibroblasts originate from resident fibroblast populations (82,83); TGF-β may play a crucial role in conversion of these highly plastic interstitial cells into myofibroblasts. TGF-β may also stimulate extracellular matrix synthesis and modulate the protease expression profile of these cells.…”

Section: Tgf-β In Regulation Of Fibroblast Phenotype and Functionmentioning

confidence: 99%

The role of transforming growth factor (TGF)-β in the infarcted myocardium

Frangogiannis

2017

J. Thorac. Dis.

119

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The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited.Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the contextdependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

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Interacting Resident Epicardium-Derived Fibroblasts and Recruited Bone Marrow Cells Form Myocardial Infarction Scar

Cited by 137 publications

References 24 publications

Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide

Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

The role of transforming growth factor (TGF)-β in the infarcted myocardium

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