Phenoconversion of Cardiac Fibroblasts to Myofibroblasts

The cardiac stroma provides tensile strength binding muscle cells and serves as structural scaffolding in the presence of continuous cyclic changes in mechanical tension. The principal stromal cell types are fibroblasts, but this designation belies their diversity and topographical differentiation from organ to organ, including the heart.1 For example, skin fibroblasts and vascular smooth muscle cells share the expression of desmin and are thereby distinguished from virtually all other fibroblasts and myofibroblasts, including those in heart.2 The term “fibroblast” designates a highly heterogenous group that exhibits distinct differentiated phenotypes in different tissues.1 The implications of these fundamental differences are unclear. Furthermore, the study of fibroblast and myofibroblast biology in specific organs is important; however, in the context of the heart it is a relatively understudied area. Recent work has revealed that ventricular fibroblast activation and cardiac fibrosis may be primary events in ventricular remodeling rather than occurring as secondary responses to cardiomyocyte injury.3 Thus, the traditional role of cardiac fibrosis as a secondary disease modifier has been called into question recently, and the need to establish the specific behavior and expression patterns of genes that characterize cardiac myofibroblasts is becoming apparent. Hypertension is marked by the development of cardiac fibrosis, and it is well established to contribute to increased risk of cardiovascular events, which can be partially alleviated with appropriate treatment.4 The interstitium of healthy heart is populated by cardiac fibroblasts, which can effect a slow turnover of fibrillar collagens and other matrix proteins.5 Fibroblasts respond to both mechanical loading and/or transforming growth factor1 stimulation by phenoconverting to contractile and hypersecretory myofibroblasts.6,7 Thus, an essential step in the onset of cardiac fibrosis is the cardiac ventricular fibroblast conversion to myofibroblastic phenotype. Myofibroblasts are the primary mediators of wound healing in the damaged ventricle, and we have demonstrated previously that they are the dominant cell type in the infarct scar.8,9 The relevance of investigating the biology of these cells in hypertrophied hearts is high, because they contribute to cardiac fibrosis and matrix remodeling through the elevated production of fibrillar and nonfibrillar collagens, as well as focal adhesion–associated proteins, respectively.8,10 Although a number of laboratories have reported on this in vitro phenoconversion in primary cells8,11 and have described a number of cytokines that are associated with this conversion and subsequent remodeling of the cardiac extracellular matrix, the cytokines of the interleukin (IL)-6 superfamily are also known to influence matrix remodeling and cardiac fibrosis.12,13