br Cardiac tissue macrophages Cardiac tissue macrophages
Cardiac tissue macrophages Cardiac tissue macrophages (cTMs), which are found in abundance in the murine heart (Fig. 1), display typical macrophage characteristics, undertaking extensive macropinocytosis and phagocytosis to sample the local microenvironment and express a wide array of PRRs such as CD14, CD64 and Lpar6 (Pinto et al., 2012) that enable rapid responses to a range of damage-associated molecular patterns. However, cTMs exhibit a distinct phenotype, closely resembling alternatively-activated M2 macrophages that are observed at late phases of tissue inflammation, secreting tissue salutary and immunomodulatory factors (Pinto et al., 2012). Moreover, cTMs produce factors such as C1q and galectins that aid phagocytosis of cellular debris and simultaneously dampen inflammation. Therefore, a presumed function of cTMs is the inhibition of aberrant inflammatory reactions that may lead to cell death, and promotion of cell survival.
Macrophages and regulation of epicardial progenitors The mammalian epicardial niche hosts multi-potent progenitor Chloroquine with the capacity to form endothelial cells, fibroblasts and smooth muscle cells (Smart et al., 2011; Chong et al., 2011). Although the relationship between macrophages and epicardial progenitors has not been characterised, the epicardium is in close contact with cTMs that are likely to modulate the activity of epicardial progenitors in the un-injured and injured heart (Pinto et al., 2014). cTMs constitutively express a number of genes involved in epicardial development and stem cell homeostasis including thymosin β4 and CEBP/β, suggesting that cTMs may play a role in epicardial development from an early stage and following injury (Pinto et al., 2014; Huang et al., 2012; Smart et al., 2007). Following cardiac injury, both resident cTMs and exogenous macrophages may be important for epicardial responses through paracrine mechanisms. Supporting this hypothesis, studies have indicated that regulation of the post-injury epicardium inflammatory milieu may be beneficial for cardiac repair and function. Indeed, injection of supernatants from ex vivo cultured epicardial progenitors improve cardiac repair after injury (Zhou et al., 2011). Moreover, adenoviral targeting of CEBP/β, a transcription factor expressed in macrophages, at the epicardium also improves cardiac repair (Huang et al., 2012). Both reports propose that modulation of epicardial paracrine environment is potentially key for the observed enhanced myocardial repair (Huang et al., 2012; Zhou et al., 2011), underscoring the potentially important role of cTMs and exogenous macrophages in regulating the post-MI inflammatory milieu and tissue repair. The finding that macrophage signalling, particularly from M2-like macrophages, enhances MSC survival, engraftment and potentially also differentiation (Ben-Mordechai et al., 2013; Freytes et al., 2013), suggests that the role of macrophage signalling may be also important for the regulation of epicardial progenitor cells to repair the damaged myocardium. However, cTM contribution to inflammatory responses at the epicardium is likely to change with age. We recently showed that cTM phenotype changes as a function of age within the epicardium resulting in a reduction of expression in chemokine/injury-sensing receptors including Cx3cr1, Lpar6, CD9, Cxcr4, Itga6 and Tgfβr1 in addition to downstream signal transduction elements (Pinto et al., 2014). Indeed, cTMs at the epicardium from aged mice (>30weeks old) are almost completely lacking Cx3cr1, which regulates macrophage responses to tissue injury (Lee et al., 2010). Therefore age-dependent loss of Cx3cr1 and other cTM injury sensing receptors may alter epicardial stem cell mobilisation and cardiac tissue repair. Moreover, with age, cTMs increase expression of pro-fibrotic elements that may alter the epicardial extracellular matrix (ECM). These include leukotriene c4 synthase, and Mmp9 which are associated with the promotion of fibrosis, collagen deposition and fibroblast proliferation (Pinto et al., 2014). ECM modification is important for stem cell homeostasis and function. ECM stiffness can regulate stem cell homing and differentiation (reviewed Discher et al., 2009) and composition and bioavailability of growth factors and cytokines (Schultz & Wysocki, 2009). Thus, cTM-mediated ECM remodelling of the epicardium is another potential mechanism whereby cTMs may regulate epicardial progenitors.