Cardiac fibroblast: the renaissance cell

Abstract

The permanent cellular constituents of the heart include cardiac fibroblasts, myocytes, endothelial cells, and vascular smooth muscle cells. Previous studies have demonstrated that there are undulating changes in cardiac cell populations during embryonic development, through neonatal development and into the adult. Transient cell populations include lymphocytes, mast cells, and macrophages, which can interact with these permanent cell types to affect cardiac function. It has also been observed that there are marked differences in the makeup of the cardiac cell populations depending on the species, which may be important when examining myocardial remodeling. Current dogma states that the fibroblast makes up the largest cell population of the heart; however, this appears to vary for different species, especially mice. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell-cell communication with myocytes, cell-cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors and cytokines, as well as potentiating blood vessel formation. Although a plethora of information is known about several of these processes, relatively little is understood about fibroblasts and their role in angiogenesis during development or cardiac remodeling. In this review, we provide insight into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart.

Figure 1. Roles of the Cardiac Fibroblast

The cardiac fibroblast responds to stimuli in various ways, including secretion of cytokines and growth factors, differentiation into a myofibroblast, proliferation and migration and altering matrix generation and degradation.

Figure 2. Sources of Fibroblasts and Myofibroblasts

The pathways leading to fibrosis involve considerable cell plasticity, with the pro-fibrotic cells being derived from several sources. Epithelial cells can be transformed into mesenchymal cells and vice versa. Mesenchymal stem cells can differentiate into cardiac fibroblasts. Fibrocytes can also differentiate into fibroblasts or myofibroblasts. Finally, pericytes surrounding the vasculature can be differentiated into myofibroblasts.

Figure 3. Organization and Interactions of Fibroblasts and Myocytes in the Heart

A) Confocal micrograph of adult rat heart stained with phalloidin (red), DAPI (blue) and WGA (green). The fibroblasts lie within the endomysial collagen in the extracellular space as previously shown. B) Transmission electron micrograph showing cardiac myocytes in contact with a cardiac fibroblast. The cardiac fibroblasts are in contact with collagen, other fibroblasts, and myocytes forming a mechanosensitive three-dimensional arrangement.

Figure 4. Cell Communication Between Cardiac Fibroblasts and Myocytes

Z-section of a cell aggregate containing cardiac fibroblasts that were dual loaded with Lucifer Yellow and CMRA and myocytes that were unloaded. Cardiac fibroblasts appear as yellow or orange cells. The orange cells are fibroblasts that have transferred their green dye to an adjacent cell (orange arrow). Note the green cells, which are myocytes that have received green dye from an adjacent fibroblast (white arrow).

Figure 5. Cardiac Fibroblasts and Endothelial Cells are Intimately Associated with One Another

A) Confocal micrograph demonstrating tight association of fibroblasts and endothelial cells (ECs) in the coronary vasculature. Mice were perfused with fluorescent microspheres (red), hearts collected and stained with DAPI (blue) to visualize nuclei and DDR2 to visualize fibroblasts (teal). Note the tight association between the fibroblasts and the vasculature. White spots are co-staining of microspheres and 1611. B) TEM imaging of adult mouse hearts illustrates the close relationship between fibroblasts and ECs. Note the pinocytotic vesicles present in the ECs. Cells in such close proximity have several avenues by which they communicate, including gap junctions and the ECM.