A key mechanism whereby macrophages may affect tissue

A key mechanism whereby macrophages may affect tissue repair and regeneration is by instructing the stem cell niche by paracrine mechanisms. In the mouse skeletal muscle injury model, macrophage-derived paracrine factors promote satellite cell survival, proliferation and differentiation in vitro and in vivo (Cantini et al., 1994; Chazaud et al., 2003). In the mouse hepatic injury model, phagocytic macrophages activate HPCs via Wnt3a signalling, to induce HSP proliferation and differentiation (Boulter et al., 2012). Depletion of macrophages sharing the HPC niche results in re-specification of HPCs to generate peri-portal biliary structures instead of hepatocytes (Boulter et al., 2012). Macrophages also occupy the haematopoietic stem cell (HSC) niche (Chow et al., 2011b; Ludin et al., 2012; Winkler et al., 2010). Macrophage depletion using either Clo-Lip, macrophage-specific genetic or antibody-mediated depletion strategies, results in egression of haematopoietic stem methylphenidate hcl (HSCs). Here, also, paracrine signalling is important with Cxcl12 playing a prominent role (Chow et al., 2011b; Ludin et al., 2012; Winkler et al., 2010; Christopher et al., 2011). Depletion of bone marrow macrophages leads to a significant decrease in Cxcl12 production (Chow et al., 2011b; Ludin et al., 2012; Winkler et al., 2010; Christopher et al., 2011), a critical factor for HSC homeostasis (Sugiyama et al., 2006). Moreover, macrophage G-CSFR is important for regulation of Cxcl12 and HSC mobilisation, with macrophage-restricted G-CSFR expression sufficient for G-CSF mediated HSC egression (Christopher et al., 2011). These observations indicate that macrophages, in particular subepicardial cTMs, may act as gatekeepers regulating progenitor cell mobilisation. Macrophages likewise positively regulate mesenchymal stem cells. In vitro experiments on cultured human MSCs demonstrate that macrophage-derived growth factors enhance MSC growth, viability, motility and secretion of paracrine factors (Freytes et al., 2013; Anton et al., 2012). MSC mobilising factors include IL-8, Mcp-1 and CCL5, which are chemotactic for MSCs (Anton et al., 2012). However, macrophage-MSC interactions are not uni-directional. MSCs transplanted to the injured myocardium induce a shift in the balance of macrophages to an M2-like phenotype (Ben-Mordechai et al., 2013). Similarly, in a spinal cord injury model, MSC transplantation shifts macrophage phenotype to an M2-like phenotype, leading to improved functional recovery (Nakajima et al., 2012). These findings are consistent with in vitro evidence that supernatants from cultured human MSCs polarise human monocyte-derived macrophages towards M2-like cells (Kim & Hematti, 2009). Finally, macrophages play a significant role in promoting cancer stem cell proliferation and activation (De Palma & Lewis, 2013). Tumour associated macrophages (TAMs), closely resembling M2 macrophages (Pucci et al., 2009; Mantovani et al., 2002), release a number of paracrine factors that regulate cancer stem cells (CSCs) (De Palma & Lewis, 2013), including those that induce tumour cells to acquire cancer stem cell-like phenotypes (Yang et al., 2013; Jinushi et al., 2011). Depletion of macrophages by either using Clo-Lip or synthetic inhibitors of macrophage colony stimulating factor 1 receptor results in a reduction in the number and activity of CSCs within tumours and increased sensitivity to chemotherapeutic agents (Yang et al., 2013; Mitchem et al., 2013). Taken together, these examples underscore the importance of macrophage-stem cell cross talk for stem cell homeostasis and mobilisation. Considering the close interaction of cTMs with the epicardium (Pinto et al., 2014), these observations indicate that cTMs may be important for epicardial progenitor cell homeostasis and potential maintenance of the progenitor cell phenotype.
Challenges and future perspectives While a significant body of work indicates that macrophages are critical for tissue homeostasis, repair and regeneration, much work is still required to delineate the precise contribution of macrophages in these processes particularly in the heart. Indeed, recent work has demonstrated that the regeneration of the mouse neonatal heart and adult axolotl heart is dependent on macrophages (Aurora et al., 2014; Godwin, Pinto, Rosenthal, unpublished data). However, the basic questions of whether macrophages are merely required for clearance of tissue debris, an essential pre-requisite process for tissue injury resolution, or whether they play a greater role in directing cell fate and organogenesis remain to be unequivocally demonstrated.