Cardiac myofibroblasts: cells out of balance. A new thematic series

What is the difference between healthy cardiac fibroblast function and that of cardiac myofibroblasts? Matrix components of the healthy heart are produced by interstitial cardiac fibroblasts[2]. These cells maintain a relatively slow turnover of fibrillar collagens[3] in normal conditions, but may respond to both mechanical loading[4] and TGF-β1 stimulation[5, 6] by a switch to a myofibroblastic phenotype wherein they express α-smooth muscle actin (αSMA)[7], synonymous with increased contractile force[8]. αSMA expression is increased in myofibroblasts in fibrotic hearts subjected to pressure or volume overload or in the infarct scar of post-MI hearts[3]. Causal factors in this conversion are compressibility of the substrate when ventricular fibroblasts are plated in vitro[9] and overexpression of R-Smads[10]. Enhanced contractility that attends this protein’s expression is believed to be important in allowing these cells to contract while bound to matrix collagens and other proteins, thereby allowing for physical remodeling of the matrix itself[11]. Thus myofibroblasts are the primary mediators of wound healing in the damaged ventricle and we have previously demonstrated that they are the dominant cell type in the infarct scar[12]. Myofibroblasts migrate to the infarct zone, restoring cellularity[13]. Their contraction confers matrix remodeling by imparting tensile force to the matrix, opposes retractile force, promotes scar contraction, activates latent TGF-β1, and reorients collagen fibrils[4, 14–16]. Investigation of these cells in hypertrophied hearts is clinically relevant as they contribute to wound healing, matrix remodeling, and eventual cardiac fibrosis through the elevated production of fibrillar and non-fibrillar collagens[17, 18].

The new thematic series to be published in this journal will touch upon topics not commonly associated with “textbook” knowledge of cardiac fibroblasts. Included in the range of topics in which we will be accepting submissions of novel research papers and review articles are: (1) the role of fibroblast and myofibroblast autophagy in the regulation of cellular function, (2) the relative contribution of migratory stem cells in populating the heart with myofibroblasts vs. endogenous conversion of fibroblasts to myofibroblasts, (3) the roles of pericytes, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), and fibrocytes in influencing cardiac extracellular matrix remodeling in heart disease, (4) microRNA influence on myofibroblast function, (5) novel signaling pathways and mechanotransduction in the regulation of myofibroblast function, (6) exploration of the role of non-collagenous proteins in the cardiac extracellular matrix, (7) developments in MMP and TIMP biology in the heart, (8) valvular interstitial cells and valve disease, and finally, (9) novel aspects of myofibroblast biology. As these areas represent novel concepts in heart disease and cardiac fibrosis and could be described as areas less well-covered in the literature, they are to be our current focus.

Why should clinicians or basic scientists care about these new developments? Part of the answer lies in the novel suggestion that cardiac fibroblasts and myofibroblasts are unique cells, e.g., distinguished by their relative specific phenotype from other fibroblastic cells. While it is well-known that the structural scaffold that exists between myocytes in the heart is composed of extracellular matrix (matrix) and mesenchymal cells and that this matrix provides an exceptionally strong means to tether and coordinate force generated via myocyte contraction, little is known of their regulation. The principal stromal cell type is fibroblasts, but this designation belies their diversity and topographic differentiation from organ to organ including the heart[19]. Thus, the term “fibroblasts” designates a highly heterogeneous group that exhibits distinct differentiated phenotypes in different tissues[19]. The implications of these fundamental differences are unclear. Further, the study of fibroblast and myofibroblast biology in specific organs is an important but relatively understudied area, especially in cardiovascular disease with attendant cardiac fibrosis. Recent novel data indicate that ventricular fibroblast activation and cardiac fibrosis are primary events in ventricular remodeling, rather than a secondary response to cardiomyocyte injury[20]. Thus the traditional role of cardiac fibrosis as a secondary disease modifier has, for the first time, been called into question[20], and the need to investigate factors that regulate cardiac myofibroblasts in various types of cardiovascular disease is apparent. For these reasons we have sought to publish a series of papers that will highlight the molecular and biochemical properties of these specific cells, and of their functioning in disease. Finally, the field of cardiac fibrosis has experienced a burgeoning level of interest and participation in investigations during the past 5 years, and this series will take advantage of this to showcase the thoughts of what some of the best minds in area are thinking.