Review article
Fibroblasts in myocardial infarction: A role in inflammation and repair

https://doi.org/10.1016/j.yjmcc.2013.11.015Get rights and content

Highlights

  • The adult mammalian heart contains abundant cardiac fibroblasts.

  • Following myocardial infarction, cardiac fibroblasts undergo dynamic phenotypic changes.

  • During the proliferative phase fibroblasts undergo myofibroblast conversion.

  • As the scar matures, myofibroblasts become quiescent and may undergo apoptosis.

  • Infarct myofibroblasts are implicated in cardiac dysfunction and arrhythmogenesis.

Abstract

Fibroblasts do not only serve as matrix-producing reparative cells, but exhibit a wide range of functions in inflammatory and immune responses, angiogenesis and neoplasia. The adult mammalian myocardium contains abundant fibroblasts enmeshed within the interstitial and perivascular extracellular matrix. The current review manuscript discusses the dynamic phenotypic and functional alterations of cardiac fibroblasts following myocardial infarction. Extensive necrosis of cardiomyocytes in the infarcted heart triggers an intense inflammatory reaction. In the early stages of infarct healing, fibroblasts become pro-inflammatory cells, activating the inflammasome and producing cytokines, chemokines and proteases. Pro-inflammatory cytokines (such as Interleukin-1) delay myofibroblast transformation, until the wound is cleared from dead cells and matrix debris. Resolution of the inflammatory infiltrate is associated with fibroblast migration, proliferation, matrix protein synthesis and myofibroblast conversion. Growth factors and matricellular proteins play an important role in myofibroblast activation during the proliferative phase of healing. Formation of a mature cross-linked scar is associated with clearance of fibroblasts, as poorly-understood inhibitory signals restrain the fibrotic response. However, in the non-infarcted remodeling myocardium, local fibroblasts may remain activated in response to volume and pressure overload and may promote interstitial fibrosis. Considering their abundance, their crucial role in cardiac inflammation and repair, and their involvement in myocardial dysfunction and arrhythmogenesis, cardiac fibroblasts may be key therapeutic targets in cardiac remodeling. This article is part of a Special Issue entitled Myocyte-Fibroblast Signalling in Myocardium.

Introduction

Fibroblasts are mesenchymal cells, abundantly distributed in connective tissues of most organs. Although traditionally viewed as matrix-producing cells that become activated following injury and participate in scar formation, fibroblasts have a diverse range of functions and exhibit remarkable plasticity, undergoing dynamic phenotypic alterations in response to changes in their microenvironment. Thus, the role of fibroblasts may extend beyond their contribution to scar formation and matrix remodeling. Experimental studies have suggested important fibroblast-mediated actions in regulating inflammation [1], in modulating oncogenic potential [2] and in stimulating angiogenesis [3]. Unfortunately, the lack of reliable tools for fibroblast-specific gene targeting has hampered efforts to understand the role of fibroblasts in tissue homeostasis and in various pathologic conditions.

The adult myocardium contains a large population of quiescent fibroblasts, enmeshed into the interstitial and perivascular matrix [4]. Due to their abundance, their strategic location and their potential for activation, cardiac fibroblasts may serve as sentinel cells that sense myocardial injury and trigger inflammatory and reparative responses. Because the adult mammalian heart has negligible regenerative capacity, cardiac repair following sudden loss of a large number of cardiomyocytes is dependent on the clearance of dead cells and on the formation of a collagen-based scar. Thus, repair of the infarcted heart requires timely activation of an inflammatory cascade to debride the wound from dead cells and matrix fragments, followed by induction of matrix-preserving signals that induce deposition of extracellular matrix. Tight temporal and spatial regulation of inflammatory and fibrogenic pathways is needed to prevent overactive responses that may accentuate injury and promote adverse remodeling and dysfunction. Fibroblasts undergo dynamic phenotypic changes following myocardial infarction and are capable of regulating the inflammatory and reparative cascade. Our review manuscript discusses the origin of fibroblasts in the healing infarct, the molecular signals responsible for fibroblast activation in the healing infarct and their involvement in repair and remodeling of the infarcted heart. Moreover, we identify potential therapeutic targets that may hold promise for treatment of patients with heart failure by interfering with fibroblast function.

Section snippets

Fibroblasts in cardiac homeostasis

Early experimental studies using scanning and transmission electron microscopy as well as gradient centrifugation have suggested that fibroblasts may outnumber cardiomyocytes in adult mammalian hearts [5], [6]. However, it is now appreciated that the relative numbers of cardiomyocytes and non-cardiomyocytes in the myocardium are likely dependent on the species studied, on the age, gender and genetic background of the subjects, and on the technique and marker used for fibroblast identification

Repair and remodeling of the infarcted heart: temporal and spatial considerations

Because fibroblasts promptly respond to alterations in their microenvironment, understanding their phenotypic changes in the infarct requires knowledge of the pathology of cardiac repair. Healing of the infarcted heart can be divided in three distinct, but overlapping phases: the inflammatory phase, the proliferative phase and the maturation phase [12]; each phase is associated with distinct fibroblast phenotypes. Massive necrosis of cardiomyocytes in the infarcted heart triggers the

Are fibroblasts key inflammatory cells in the infarcted myocardium?

Twenty to thirty minutes of severe ischemia is sufficient to induce irreversible cardiomyocyte injury. Thus, prolonged cessation of blood flow in myocardial infarction causes extensive necrosis of cardiomyocytes in the area at risk. In contrast, interstitial non-cardiomyocytes are much less susceptible to ischemic injury. Because of their resistance to ischemic death, their wide distribution in the cardiac interstitium, their interaction with cardiomyocytes and their potential as sources of

Fibroblasts during the proliferative phase

During the proliferative phase of healing, fibroblasts become the dominant cell type in the infarcted myocardium and undergo dramatic phenotypic changes (Fig. 3). Removal of pro-inflammatory signals such as IL-1β and Interferon-γ-inducible Protein (IP)-10, allows unopposed growth factor signaling in cardiac fibroblasts, promoting a matrix-preserving, proliferative myofibroblast phenotype. High proliferative activity, migration through the provisional matrix network of the infarct, expression

The fate of the myofibroblasts during infarct maturation

Formation of a collagen-based matrix marks the end of the proliferative phase and sets the stage for maturation of the scar, a poorly understood process that is characterized by matrix cross-linking and progressive loss of the cellular elements. Myofibroblast density is markedly reduced in mature infarcts; cellular depletion is accentuated and accelerated in mouse models of infarction, where large areas of myocardium are replaced by thin strips of collagenous tissue [37]. Although apoptosis has

The fibroblasts in the remodeling non-infarcted myocardium. Dynamic effectors in heart failure?

While large numbers of infarct myofibroblasts undergo apoptosis, the remote remodeling non-infarcted myocardium is subjected to pressure and volume overload; both pathophysiologic conditions expected to cause chronic activation of the local fibroblast population. Studies systematically examining the characteristics of fibroblasts in the remodeling non-infarcted myocardium are lacking. However, insights derived from experimental animal models suggest that pressure and volume overload have

Do activated myofibroblasts contribute to arrhythmogenesis following myocardial infarction?

A growing body of evidence suggests that cardiac fibroblasts may be involved in the generation and propagation of arrhythmias [94], [95]. Infiltration of the infarcted myocardium with abundant myofibroblasts may alter cardiac electrophysiology by creating a barrier that blocks propagation of the electrical impulse, delaying conduction and promoting formation of reentry circuits [95]. In addition to these mechanical effects, electrical coupling between fibroblasts and cardiomyocytes may promote

Fibroblasts as therapeutic targets in myocardial infarction

Because remodeling of the infarcted heart is dependent on the mechanical properties of the scar, the effects of fibroblasts in the infarcted and remodeling myocardium have important functional implications. As the main cellular effectors in matrix remodeling, and as important modulators of the inflammatory and reparative response, fibroblasts are promising therapeutic targets. The actions of certain pharmacologic approaches with well-documented benefit in patients with myocardial infarction may

Conclusions

Due to their abundance, strategic location, phenotypic plasticity and ability to secrete a wide range of inflammatory mediators, reparative growth factors, proteases, structural extracellular matrix proteins and matricellular macromolecules, cardiac fibroblasts are ideally suited as key effector cells in healing infarcts. Unfortunately, our understanding of their in vivo role is hampered by the absence of reliable and specific fibroblast markers and by challenges in developing

Disclosures

None.

Acknowledgments

Dr Frangogiannis' laboratory is supported by the NIH grants R01 HL76246 and R01 HL85440 and the Wilf Family Cardiovascular Research Institute.

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