Cardiac Fibroblasts

There are important phenotypic differences between fibroblasts from different tissues and physiological conditions. Fibroblasts are mesenchymal cells that are associated with various forms of connective tissue. These are generally characterized by the absence of a basement membrane and its tendency to form cytoplasmic extensions.They contain an oval nucleus, large plasma reticulum, prominent Golgi apparatus and abundant granular material. It has been recently shown that the protein DDR2 (discoidin domain receptor 2), a collagen receptor, is expressed in cardiac fibroblasts (Camelliti P, Borg TK, 2005). Additionally, fibroblasts generally express vimentin, FSP-1 (fibroblast-specific protein), periostin, and several important molecules of the ECM (Banerjee I, fusel JW, 2007 - Goldsmith EC, Zhang X, 2009).
Despite the identification of fibroblasts in the late 19th century, yet relatively little is known about the origin and development of cardiac fibroblasts. As already mentioned, they are the most abundant cell type in the mature heart and its population is denser around the sinoatrial node (Camelliti P, Green CR, 2004 - Kohl P, 2004), in order to confer a total electrical isolation. It is thought that heart fibroblastsarise from various sources throughout the different stages of cardiac development, but the study of these cell lines is complicated due to the absence of lineage-specific markers, resulting in a wide variety of phenotypical descriptions . It is considered that the mesenchymal cells that give rise to cardiac fibroblasts mainly derived from the embryonic epicardium (Mikawa T, Gourdie RG, 2006 - Lie-Venema H, van den Akker NMS, 2007). The epicardium is the last layer embryo to develop, and originates from a transient proepicardium (Wessels A, Perez-Pomares JM, 2004) consisting of an accumulation of vesicular fingerlike protrusions of the pericardial coelomic mesothelium formed near the venous trunk of the embryonic heart. As a result of endothelial-mesenchymal transformation proepicardium, the MEC is populated with mesenchymal cells that migrate and lining the embryonic heart to form the epicardium (Wessels A, Perez-Pomares JM, 2004). It is thought that after the endothelial-mesenchymal transformation of epicardial cells, the epicardium derived cells (EPDCs) give rise to most cardiac fibroblasts, the subepicardial mesenchymal undifferentiated endothelial cells and vascular smooth muscle cells. Therefore, cardiac fibroblasts arise from the epicardium-derived cells, either by endothelial-mesenchymal transformation from the ventricular surface (Muñoz-Chápuli, 1997 - Mahtab EA, 2008), or invading the ventricular and atrial walls and migrate through fibrous ring (annulus fibrous) (Gittenberger-de Groot AC, 1998). In fetal stages, fibroblasts can also develop from mesoangioblasts, multipotent precursor cells and vascular mesodermal tissues (Cossu G and Bianco P, 2003). 

The multiple roles of cardiac fibroblasts. 

The cardiac fibroblasts are specifically positioned to contribute to the structural, biochemical, mechanical and electrical properties of normal heart (Camelliti P, Borg TK, 2005). First, the contribution of cardiac fibroblasts is absolutely essential in the synthesis and maintenance of extracellular matrix components, the three-dimensional framework that integrates the activity of individual cells to coordinate the contractile function of myocardium (Gaudesius G, Miragoli M 2003 - M. Eghbali, 1992 - Zeisberg EM, Tarnavski O, 2007 - Ng CP, Hinz B, 2005). The cardiac fibroblasts are also essential for other bodily functions determined by dynamic cell-cell interactions and cell-ECM and are essential for maintaining normal cardiac function. In this role, the fibroblasts respond to various mechanical and electrical stimuli, in addition to chemical stimuli such as hormones, growth factors and cytokines (Kohl et al., 2005).The cardiac fibroblasts are also a source of growth factors with paracrine activity (Akiyama-Uchida Y, Ashizawa N, 2004) and by themselves, sources of various cytokines and growth factors.
The cardiac fibroblasts are not excitable and do not respond to electrical stimuli with the generation of an action potential. However, through electrical interactions, the cardiac fibroblasts can synchronize and possibly transmit the electrical activity in the multicellular cardiac tissue (Camelliti P, Green CR, 2004 - Gaudesius G, Miragoli M, 2003). When electrically coupled, cardiac fibroblasts can act as current sinks and thereby reduce the driving speed and maximum level of depolarization of action potential (Miragoli M, Gaudesius G, 2006 - Kohl P, Kamkin AG, 1994).


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Submitted by: Barallobre-Barreiro J, Spain