Function and fate of myofibroblasts after myocardial infarction

Abstract

The importance of cardiac fibroblasts in the regulation of myocardial remodelling following myocardial infarction (MI) is becoming increasingly recognised. Studies over the last few decades have reinforced the concept that cardiac fibroblasts are much more than simple homeostatic regulators of extracellular matrix turnover, but are integrally involved in all aspects of the repair and remodelling of the heart that occurs following MI. The plasticity of fibroblasts is due in part to their ability to undergo differentiation into myofibroblasts. Myofibroblasts are specialised cells that possess a more contractile and synthetic phenotype than fibroblasts, enabling them to effectively repair and remodel the cardiac interstitium to manage the local devastation caused by MI. However, in addition to their key role in cardiac restoration and healing, persistence of myofibroblast activation can drive pathological fibrosis, resulting in arrhythmias, myocardial stiffness and progression to heart failure. The aim of this review is to give an appreciation of both the beneficial and detrimental roles of the myofibroblast in the remodelling heart, to describe some of the major regulatory mechanisms controlling myofibroblast differentiation including recent advances in the microRNA field, and to consider how this cell type could be exploited therapeutically.

Figure 1

Summary of the influence of myofibroblast density on post-myocardial infarction remodelling. Low myofibroblast density in the infarct area results in a poorly structured, expansive and vulnerable scar that is prone to rupture or leads to systolic dysfunction and subsequent adverse myocardial remodelling. Although high myofibroblast density is important for a robust, contractile scar, excessive myofibroblast numbers (particularly in the remote myocardium away from the original infarct) drives fibrosis and myocardial stiffness, resulting in contractile dysfunction, arrhythmia and heart failure progression.

Figure 2

Summary of potential roles of microRNAs in regulating cardiac myofibroblast phenotype and function. microRNA (miR)-24, miR-30 and miR-133a inhibit transforming growth factor beta (TGF-β)-induced differentiation of resident cardiac myofibroblasts to myofibroblasts either directly or by reducing TGF-β levels. miR-21 and miR-125b stimulate conversion of endothelial cells to myofibroblasts via endothelial–mesenchymal transition (EndMT). Synthesis of extracellular matrix (ECM) proteins (for example, collagen) by myofibroblasts is upregulated by miR-21, miR-29 and miR-30, and miR-21 also stimulates cell migration and survival. In contrast, miR-29 inhibits cell survival. See main text for details.