Members of this family are produced as inactive precursors that are maturated in the trans-golgi into large latent Adriamycin complexes that are released to the ECM. After a conformational change (controlled by integrins, ROS, pH, and others), active TGFβs are exposed to their receptor binding sites. These signal largely through an

Smad2/3-dependent mechanism leading to the recruitment of Smad4 and the induction of gene expression ( Kaminska et al., 2013). TGFβ and TGFβ receptor expression has been found in every cell type of the CNS. It has effects on neuronal survival, microglia migration, and phagocytosis and has angiogenic potential on cerebral endothelial cells ( Beck and Schachtrup, 2012). Its most documented effects, however, are carried out in astrocytes by promoting its migration, inhibiting its proliferation, and increasing the production of ECM components ( Kaminska et al., 2013). Considered tissue-resident macrophages much like Kupffer cells for the liver or histiocytes in connective tissues, microglia are the only cells in the CNS that are of hematopoietic origin (Soulet and Rivest, 2008b). Fate-mapping analysis has demonstrated that hematopoietic precursors from the yolk sac populate the CNS before the eighth embryonic day in mice (Ginhoux et al., 2010). Once present, microglia are capable of self-renewal and do

not require replenishment for circulating monocytic precursors (Ajami Ergoloid et al., 2007). They are thus distinct from the monocyte lineage of cells and other tissue-specific macrophages such as Kuppfer cells Stem Cells inhibitor in the liver, for which the maintenance is dependent upon the recruitment of bone marrow-derived cells (BMDCs) from the circulation (Klein et al., 2007). In the CNS, initial reports suggested that the recruitment of BMDCs was an active event in normal physiology (Simard and Rivest, 2004). After an intense debate on the subject (Soulet and Rivest, 2008a), a consensus appears to have been reached following new experimental evidence that BMDC recruitment is a marginal effect in normal physiology (Lampron

et al., 2012) but important in pathological conditions affecting the integrity of the CNS such as stroke (Schilling et al., 2009), multiple sclerosis (Floris et al., 2004), amyotrophic lateral sclerosis (Vaknin et al., 2011), and others. This recruitment can be beneficial or harmful, depending on the condition studied (Shechter and Schwartz, 2013). In their native state, microglia are highly ramified cells with a small cellular body. Its extended processes allow microglia to rapidly sense the presence of tissue damages or signs of infections through PRRs. Microglia are highly plastic cells, they respond rapidly to the danger signals released by injured cells and secrete appropriate cytokines both to clear debris and to attract other microglial cells (Soulet and Rivest, 2008b).