Fibroblasts in post-infarction inflammation and cardiac repair

Abstract

Fibroblasts are the predominant cell type in the cardiac interstitium. As the main matrix-producing cells in the adult mammalian heart, fibroblasts maintain the integrity of the extracellular matrix network, thus preserving geometry and function. Following myocardial infarction fibroblasts undergo dynamic phenotypic alterations and direct the reparative response. Due to their strategic location, cardiac fibroblasts serve as sentinel cells that sense injury and activate the inflammasome secreting cytokines and chemokines. During the proliferative phase of healing, infarct fibroblasts undergo myofibroblast transdifferentiation forming stress fibers and expressing contractile proteins (such as α-smooth muscle actin). Mechanical stress, Transforming Growth Factor (TGF)-β/Smad3 signaling and alterations in the composition of the extracellular matrix induce acquisition of the myofibroblast phenotype. In the highly cellular and growth factor-rich environment of the infarct, activated myofibroblasts produce matrix proteins, proteases and their inhibitors regulating matrix metabolism. As the infarct matures, “stress-shielding” of myofibroblasts by the cross-linked matrix and growth factor withdrawal may induce quiescence and ultimately cause apoptotic death. Because of their critical role in post-infarction cardiac remodeling, fibroblasts are promising therapeutic targets following myocardial infarction. However, the complexity of fibroblast functions and the pathophysiologic heterogeneity of post-infarction remodeling in the clinical context discourage oversimplified approaches in clinical translation.

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

“…(Myo)fibroblasts have different roles in the different phases. 4,10 In the initial phase, the fibroblasts act as local immune modulators and are the main effectors of fibrogenesis. 1,[4][5][6]20 In the subsequent proliferative phase of healing, fibroblasts further differentiate into myofibroblasts that not only have an augmented matrixsynthetic phenotype but also express the contractile protein α-SMA.…”

“…2,3 Cardiac fibroblasts, which account for up to 70% of the cells present in the myocardium, regulate extracellular matrix (ECM) turnover, and have an essential role in cardiac homeostasis. Fibroblasts are more resistant to ischemia than cardiomyocytes, [4][5][6] and prolonged myocardial ischemia results in death of particularly the cardiomyocytes, whereas the fibroblasts survive. Fibroblasts have therefore been proposed to be a therapeutic target to influence the healing process of the infarcted myocardium.…”

“…These (myo)fibroblasts have key roles both in the initial inflammatory phase as well as in the subsequent proliferative phase of the postinfarction response, which together lead to the formation of a stable, collagen-rich scar. 4 Thus, increasing myofibroblast presence shortly after MI has been proposed to promote scar contraction and limit LV dilation. 1,4,10 Fibroblast migration is inhibited by Wnt/Frizzled (Fzd) signaling.…”

“…4 Thus, increasing myofibroblast presence shortly after MI has been proposed to promote scar contraction and limit LV dilation. 1,4,10 Fibroblast migration is inhibited by Wnt/Frizzled (Fzd) signaling. Targeting the Wnt signaling pathway by modulating its ligand, the Fzd receptors, through UM206, an antagonist of Fzd1 and Fzd2, has been shown to promote fibroblast migration, limit infarct size, and attenuate adverse remodeling after infarction induced by permanent ligation of the coronary artery in mice.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…CXCL-1, 2, 5 and 8), and express specific neutrophil-binding adhesion molecules including ICAM-1 and E-selectin [88,[90][91][92][93], as well as the matricellular protein TN-C [94]. Thus, CF may contribute to the inflammatory milieu that occurs in the myocardium early after MI [10,95]. In addition to this inflammatory response, we [7,88,93,94,[96][97][98] and others [61,99,100] have demonstrated that CF alter the balance of cardiac ECM turnover in favour of degradation in response to IL-1; for example by increasing secretion of MMPs, decreasing collagen synthesis and decreasing expression of profibrotic factors (e.g.…”