Cardiac Fibroblasts

Cardiac fibroblasts (CFs) are cells of mesenchymal origin, which are characterized by their capacity to produce extracellular matrix (ECM) and collagen, participate in fibrosis, ECM remodeling, tissue repair, and scar formation (Dostal et al., 2015).

Although the percentage of fibroblasts in the heart is controversial, the CFs contribute to structural, biochemical, mechanical and electrical properties of the myocardium, as well as are responsible for cardiac remodeling and fibrosis after injury cannot be despised (Camelliti et al., 2005; Porter and Turner, 2009; Souders et al., 2009).

1.3.1 Origins and development of cardiac fibroblasts

Resident CFs are predominantly generated during embryonic development from the epicardium and endocardium through epithelial-to-mesenchymal transition (EMT) (Ali et al., 2014; Moore-Morris et al., 2014) (Figure2). The endothelial line and vasculature of heart chambers are formed from the endocardial component and undergo EMT to generate fibroblasts during development, while the epicardium component formulates the outermost layer of the heart, as well as interstitial fibroblasts and smooth muscle cells (Furtado et al., 2016). Recent studies showed that endothelial derived fibroblasts are found mainly in the interventricular septum in the adult heart, whereas epithelial derived fibroblasts occupy the free walls (Ali et al., 2014; Moore-Morris et al., 2014). Additionally, the neural crest also contributes a small portion to the fibroblasts pool, which is found in the outflow tract region of the heart (Waldo et al., 1998) and right atrium myocardium (Ali et al., 2014).

Compared with resident CFs, fibroblasts in the injured heart are believed to have different origins (Figure2) (Tallquist and Molkentin, 2017). The sources of activated CFs in response to various pathological insults remain unclear. Studies suggest that activated myofibroblasts in injured hearts primarily arise from the proliferation and activation of resident fibroblasts of both epicardium and endocardium origin, because these cells are extremely sensitive to pathological stimuli (Ali et al., 2014;

Moore-Morris et al., 2014). Furthermore, a number of non-fibroblast cellular sources have been proposed as contributors to myofibroblasts population, including endothelial cells, hematopoietic bone marrow–derived cells or immune cells, progenitor perivascular cells, and adult epicardium (Reviewed by Tallquist and Molkentin, 2017).

1.3.2 The role of fibroblasts in the heart

1.3.2.1 The role of fibroblasts in the healthy heart

The function of fibroblasts in the adult heart is still poorly understood. In the healthy heart, fibroblasts are existing in a quiescent state (Chistiakov et al., 2016).

They are called “sentinel cells” due to their ability to detect and respond to a variety of different stimuli such as chemical signals (including autocrine or paracrine fashion of growth factors, cytokines, and hormones), mechanical signals (including changes in contraction, stretch, and pressure), and electrical signals (involving the opening and closing of ion channels, as well as the connexins) (Souders et al., 2009).

Apart from this, fibroblasts play a crucial role in synthesis and deposition of extracellular matrix (ECM) to help keep normal cardiac function. The ECM consist of collagens (type 1 and type 3), glycoproteins, proteoglycans, cytokines, growth factors, and proteases (Bowers et al., 2010; Fan et al., 2012). Homeostasis of the ECM contributes to structural scaffold for cardiomyocytes and other cells. They exert mechanical forces through the cardiac tissue, and communicate mechanical signals to cells through cell surface ECM receptors (Bowers et al., 2010). For normal cardiac function, fibroblasts are continually subjected to mechanical stretch.

Appropriate regulation of these mechanical signals is important to preserving normal cardiac function (Catalucci et al., 2008). The ECM synthesis, degradation, and composition interplay with chemical, electrical, and mechanical signals, which play a key role in sustaining normal cardiac output (Dostal et al., 2015).

CFs are also involved in cell-cell communication, secreting growth factors, cytokines, electrical conduction and promoting blood vessel formation (Souders et al., 2009). With these roles in the heart, CFs are not only keeping proper cardiac function,but also play a critical role in the injured heart.

1.3.2.2 The role of fibroblasts in the injured heart

CFs respond to pathological insults by differentiation into myofibroblasts. Following cardiac injury, chemical signals (i.e. TGFβ, Angiotensin II , FGF2, the IL-6 Family, IL-33 etc.) are activated and affect fibroblasts function in an autocrine and/or paracrine manner (Kakkar and Lee, 2010; Souders et al., 2009). These signals

can change gene and protein expression, cell proliferation, and cell migration of fibroblasts, to promote wound healing and scar formation (Souders et al., 2009).

During myocardial injury, CFs become activated and undergo phenotypic conversion through the overexpression of cytoskeletal smooth muscle actin, secretion of various pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and pro-fibrotic cytokines (TGF-β) (Kawaguchi et al., 2011; Lajiness and Conway, 2014;

Segura et al., 2014).

To respond to the various stimuli, myofibroblasts start to proliferate, migrate and refit the cardiac interstitium through increasing secretion of matrix metalloproteinases (MMPs) and collagen (Brown et al., 2005; Sun and Weber, 2000). Meanwhile, CFs secrete quantities of growth factors and cytokines, especially IL-1β, IL-6 and tumor necrosis factor-α (TNF-α), which conversely activates MMPs leading to excessive ECM degradation, further contribute to cardiac remodeling and have profound effects on cardiac function (Brown et al., (Brown et al., 2005). Myofibroblasts is a part of the hallmark of pathophysiological cardiac remodeling (Humphries and Reynolds, 2009; Kong et al., 2014).

Furthermore, CFs also participate in blood vessel formation during development and potential disease, but the precise role of these cells in the angiogenic process remains unclear (Bowers et al., 2012). Fibroblasts are closely related to endothelial cells which are known to express pro-angiogenic (FGF and VEGF) and anti-angiogenic cytokines (PDGF and CTGF) (Murakami and Simons, 2008; Zhao and Eghbali-Webb, 2001). Moreover, fibroblasts also express and secrete other factors, such as MMPs and tissue inhibitors of metalloproteinases (TIMPs), leading to activation or inhibition of angiogenesis (Liu et al., 2008; Powell et al., 1999). Taken together, fibroblasts contribute to vascular remodeling after injury by expression of angiogenic and anti-angiogenic factors.