The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium

Abstract

Cardiac fibroblasts are key cellular effectors of cardiac repair; their phenotype and function are modulated by interactions with extracellular matrix proteins. This review manuscript discusses the effects of the extracellular matrix on the inflammatory and reparative properties of fibroblasts in the infarcted myocardium. Early generation of matrix fragments in the infarct induces a pro-inflammatory and matrix-degrading fibroblast phenotype. Formation of a fibrin/fibronectin-rich provisional matrix serves as a conduit for migration of fibroblasts into the infarcted area. Induction of ED-A fibronectin and nonfibrillar collagens may contribute to myofibroblast transdifferentiation. Upregulation of matricellular proteins promotes transduction of growth factor and cytokine-mediated signals. As the scar matures, matrix cross-linking, clearance of matricellular proteins, and reduced growth factor signaling cause deactivation and apoptosis of reparative infarct fibroblasts. Understanding the effects of matrix components on infarct fibroblasts may guide the design of peptides that reproduce, or inhibit, specific matricellular functions, attenuating adverse remodeling.

Figure 1

Matrix-fibroblast interactions during the inflammatory phase of infarct healing. Rapid protease activation in the infarcted heart generates collagen (Col) and fibronectin (Fn) fragments; pro-inflammatory low molecular weight hyaluronan (LMWH) fragments are also generated. Matrix fragments may induce pro-inflammatory fibroblast activation; moreover, fibronectin fragments are known to induce matrix metalloproteinase (MMP) expression. Fibrinogen extravasation into the infarcted area may also induce inflammatory signaling in fibroblasts.

Figure 2

A fibrin/fibronectin-based provisional matrix serves as a scaffold for fibroblast migration into the infarct. Immunohistochemical staining shows fibrin(ogen) localization in a canine infarct after 1h of ischemia and 24h of reperfusion (A). Fibrin deposition demarcates the infarct (black staining). After 7 days of reperfusion fibrin is incorporated into an organized provisional matrix network (B). C: Fibronectin incorporation into the matrix is crucial for fibroblast migration through interactions that involve integrins.

Figure 3

The prototypical matricellular protein thrombospondin (TSP)-1 is upregulated in the infarct border zone and may regulate fibroblast responses. Immunohistochemical staining shows a strikingly selective deposition of TSP-1 in the border zone following canine myocardial infarction (A- arrows). Serial section staining combines CD31 labeling (black) to identify endothelial cells and α-SMA staining (red) to label myofibroblasts as spindle-shaped cells located outside the vascular media (B- arrows). Note the abundance of myofibroblasts in the TSP-1-rich border zone. C: TSP-1 is a crucial TGF-β activator. TSP-1 acts by directly binding the Latency-Associated Peptide (LAP) inducing a conformational change that makes the TGF-β dimer accessible to its receptor.