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Review
. 2019 Jun 24;4(3):449-467.
doi: 10.1016/j.jacbts.2019.02.006. eCollection 2019 Jun.

Fibroblasts in the Infarcted, Remodeling, and Failing Heart

Claudio Humeres  1 , Nikolaos G Frangogiannis  1
Affiliations
Review

Fibroblasts in the Infarcted, Remodeling, and Failing Heart

Claudio Humeres et al. JACC Basic Transl Sci. .

Abstract

Expansion and activation of fibroblasts following cardiac injury is important for repair but may also contribute to fibrosis, remodeling, and dysfunction. The authors discuss the dynamic alterations of fibroblasts in failing and remodeling myocardium. Emerging concepts suggest that fibroblasts are not unidimensional cells that act exclusively by secreting extracellular matrix proteins, thus promoting fibrosis and diastolic dysfunction. In addition to their involvement in extracellular matrix expansion, activated fibroblasts may also exert protective actions, preserving the cardiac extracellular matrix, transducing survival signals to cardiomyocytes, and regulating inflammation and angiogenesis. The functional diversity of cardiac fibroblasts may reflect their phenotypic heterogeneity.

Keywords: AT1, angiotensin type 1; ECM, extracellular matrix; FAK, focal adhesion kinase; FGF, fibroblast growth factor; IL, interleukin; MAPK, mitogen-activated protein kinase; MRTF, myocardin-related transcription factor; PDGF, platelet-derived growth factor; RNA, ribonucleic acid; ROCK, Rho-associated coiled-coil containing kinase; ROS, reactive oxygen species; SMA, smooth muscle actin; TGF, transforming growth factor; TRP, transient receptor potential; cytokines; extracellular matrix; fibroblast; infarction; lncRNA, long noncoding ribonucleic acid; miRNA, micro–ribonucleic acid; remodeling.

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Figures

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Graphical abstract
Central Illustration
Central Illustration
Functional Diversity of Fibroblasts in the Infarcted Myocardium In the dynamic environment of the infarcted heart, cardiac fibroblasts expand, undergo phenotypic changes, and are implicated in a wide range of functions. Coronary occlusion causes death of cardiomyocytes in the area of injury. During the inflammatory phase of infarct healing, Damage-Associated Molecular Patterns (DAMPs) released by dying cells activate a pro-inflammatory phenotype in cardiac fibroblasts that secrete cytokines (such as IL-1, TNF-α, and GM-CSF), and chemokines (such as CCL2) contributing to recruitment and activation of leukocytes. Cytokine-stimulated fibroblasts also secrete matrix metalloproteinases (MMPs), promoting extracellular matrix degradation and release of pro-inflammatory matrix fragments. Some studies have suggested that infarct fibroblasts may also function as phagocytic cells; however, considering the abundance of macrophages in the healing infarct the relative contribution of “phagocytic fibroblasts” remains unclear. Clearance of the infarcted heart from dead cells stimulates anti-inflammatory signals, leading to suppression of inflammation and transition to the proliferative phase of infarct healing. Fibroblasts expand, predominantly through recruitment of resident populations and undergo myofibroblast conversion, incorporating α-SMA into cytoskeletal stress fibers. Activated myofibroblasts are the main matrix-synthetic cells in the infarcted heart and produce both structural extracellular matrix proteins and matricellular macromolecules. In addition to their contribution in matrix production, fibroblast populations may also contribute to regulation of the angiogenic response and may regulate macrophage phenotype. During scar maturation fibroblasts exhibit disassembly of α-SMA-decorated stress fibers, and may produce matrix-crosslinking enzymes such as lysyl-oxidases (LOX). Reduction of fibroblast numbers in mature scars has been suggested to involve activation of apoptosis. The molecular basis for the phenotypic transitions of cardiac fibroblasts in the phases of infarct healing remains poorly understood. The functional diversity of fibroblasts in the infarcted heart may reflect sequential activation of distinct fibroblast subpopulations, or may result from coordinated responses of the fibroblasts to the dynamic changes in their microenvironment.
Figure 1
Figure 1
Fibroblasts in the Inflammatory Phase of Infarct Healing During the inflammatory phase of infarct healing, cardiac fibroblasts secrete proinflammatory mediators and matrix-degrading proteases. Damage-associated molecular patterns (DAMPs) released by necrotic cells and matrix fragments activate Toll-like receptor signaling in cardiac fibroblasts. Proinflammatory cytokines (such as interleukin [IL]–1β and tumor necrosis factor [TNF]–α) released by endothelial cells, immune cells, and cardiomyocytes and activation of reactive oxygen species (ROS) accentuate fibroblast inflammatory activity. IL-1/IL-1RI signaling has been suggested to reduce α-smooth muscle actin (α-SMA) expression, preventing myofibroblast conversion. Cytokines and chemokines (such as IL-1β, TNF-α, IL-6, and granulocyte/macrophage colony-stimulating factor [GM-CSF]) secreted by activated fibroblasts may contribute to the recruitment of leukocytes, whereas protease release may promote matrix degradation. Considering that several other cell types are capable of secreting inflammatory mediators, the relative contribution of fibroblasts is unclear. The cartoon was designed using Servier Medical Art (https://smart.servier.com). DNA = deoxyribonucleic acid; HMGB1 = high-mobility group protein B1; MMP = matrix metalloproteinase; TNFR = tumor necrosis factor receptor.
Figure 2
Figure 2
Fibroblasts in the Proliferative Phase of Infarct Healing During the proliferative phase of infarct healing, fibrogenic growth factors and neurohumoral mediators trigger myofibroblast conversion and stimulate fibroblast proliferation, migration, and activation. A wide range of fibrogenic mediators, induced during the proliferative phase of cardiac repair, are implicated in myofibroblast activation. Neurohumoral mediators, such as angiotensin II (AngII), aldosterone, and norepinephrine (NE), growth factors (transforming growth factor [TGF]-βs, fibroblast growth factors [FGFs], platelet-derived growth factors [PDGFs]), and specialized matrix proteins, such as ED-A fibronectin and matricellular proteins cooperate to activate intracellular signaling pathways that promote myofibroblast conversion and proliferation and modulate expression of extracellular matrix (ECM) proteins and of genes associated with matrix metabolism. The cartoon was designed using Servier Medical Art (https://smart.servier.com). AR = adrenergic receptor; ET = endothelin; MMP = matrix metalloproteinase; NF = nuclear factor; ROS = reactive oxygen species; SMA = smooth muscle actin; TIMP = tissue inhibitor of metalloproteinase.
Figure 3
Figure 3
The Phenotypic Heterogeneity of Cardiac Fibroblast Populations May Explain Their Functional Diversity in Injured and Remodeling Hearts In the pressure-overloaded myocardium, mechanical stress activates mechanosensitive signaling pathways in cardiac fibroblasts that may involve integrins (ITGs) and stress-activated ion channels (such as transient receptor potential [TRP] channels). Traditional views consider the fibroblasts as matrix-producing cells that secrete large amounts of fibrillar and nonfibrillar collagens, increasing extracellular matrix (ECM) deposition and promoting fibrosis and diastolic dysfunction. However, recent evidence challenges this unidimensional view of fibroblasts, suggesting that they may also play protective roles, by preserving the ECM, thus preventing generation of proinflammatory matrix fragments and by transducing prosurvival cascades in cardiomyocytes. Secretion of matricellular proteins that bind to the structural components of the ECM and modulate signaling responses and release of micro–ribonucleic acid (miRNA)–containing exosomes that may modulate cardiomyocyte responses represent major additional mechanisms implicated in fibroblast actions. The diverse effects of fibroblasts in vivo may reflect their phenotypic heterogeneity, as different fibroblast subsets may exert distinct actions. MMP = matrix metalloproteinase; TIMP = tissue inhibitor of metalloproteinase.
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