Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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heart. Moreover, they play a pivotal role in cardiac development, remodeling, and

regeneration [ 4 , 5 ].

It is well-known that cardiac fibroblasts are generated during embryogenesis

through a process known as the epithelial-to-mesenchymal transition [ 6 ]. The dis-

covery of epicardium-specific genes in the mouse, such as Tcf21, Tbx18, and WT1,

strongly support this theory [ 7 ].

Despite the fact that fibroblasts have been studied for many years, there is no

universal molecular marker used to track them in vitro or in vivo. This is primarily

because all known markers are also expressed by many other cell types within the

heart. In pioneering studies, fibroblasts were originally characterized according to

their morphological features, proliferation activity, gene expression, and develop-

mental origin [ 8 – 11 ]. This also applied to the fibroblasts of the heart, necessitating

the combining of various markers for their identification. Several markers have been

used recently to identify cardiac fibroblasts, such as CD90 (also known as Thy1),

fibroblast-specific protein 1, discoidin domain receptor 2, fibronectin, vimentin, and

collagen types I and III [ 12 ]. More recently, it was shown that activated fibroblasts

are enriched for fibroblast-activating protein and alpha-smooth muscle actin [ 13 ,

14 ]. Other suitable markers are Tcf21 and platelet-derived growth factor receptor

alpha. These are responsible for fibroblast differentiation and are known to be

expressed in adult fibroblasts [ 15 , 16 ]. However, TCF21 expression is very difficult

to detect by immunohistochemistry and platelet-derived growth factor receptor

alpha is also expressed by several populations of stem cells within the heart [ 17 ].

Another robust marker of cardiac fibroblasts is mEF-SK4, but it must be colocalized

with CD31 and CD34 to exclude hematopoietic and endothelial cells [ 2 ].

Cardiac fibroblasts play an important role in the synthesis and degradation of

cardiac extracellular matrix. They also mediate many physiological and pathologi-

cal processes that contribute to the structural, biomechanical, biochemical, and

electrical properties of the heart.

Cardiac fibroblasts are highly metabolically active cells and they produce an

abundance of interstitial collagen, proteoglycans, glycoproteins, growth factors,

cytokines, matrikines, and proteases, which influence the composition, function,

and remodeling of the extracellular matrix [ 18 ]. They form a three-dimensional

network for myocytes and other cardiac cells. Moreover, they are involved in the

distribution of mechanical forces within the heart [ 19 ]. Cardiac fibroblasts respond

to changes in the cellular environment caused by physical exercise by modulating

integrin expression. This is associated with changes in cell migration [ 20 ].

Remodeling and other alterations in the organization of the myocardium are crucial

processes that help the heart adapt to changes as a result of physiological or patho-

logical events [ 21 ]. Cardiac fibroblasts are the most influential cell types involved in

this process. For example, after cardiac injury, fibroblasts are strongly influenced by

various bioactive molecules, which promote changes in fibroblast gene expression.

They also affect cell migration to damaged regions to promote regeneration and scar

formation [ 22 ]. Moreover, cardiac fibroblasts differentiate into myofibroblasts,

which produce collagen, fibronectin, and contractile proteins [ 23 ].

8 The Non-cardiomyocyte Cells of the Heart. Their Possible Roles...