br Acknowledgements This work was supported
Acknowledgements This work was supported by the IRET Foundation (2015-2016), Ozzano Emilia, Italy (no-profit organization), in the frame of the “Step-by-step” POR-FESR 2016-2020 Emilia Romagna Region project.
Introduction Resident neural stem cells (NSCs) persist in the adult mammalian central nervous system (CNS) and encourage the search for potential treatments for neurodegenerative and acute phosphodiesterase inhibitors diseases. Full potential stem cells (type B or astrocytes-like cells) line in the subventricular zone (SVZ) along the wall of the lateral ventricles in the brain. These cells are capable of proliferate, increasing the pool of progenitor cells through the generation of transient amplifying cells (type C cells) (Alvarez-Buylla and Garcia-Verdugo, 2002; Doetsch et al., 1997). The SVZ neurogenic niche comprises many components such as the vascular system, extracellular matrix, microglia, astrocytes, neurons, and cerebrospinal fluid (CSF), representing a countless source of stimuli to NSCs (Falcao et al., 2012; Lim and Alvarez-Buylla, 2014; Walton et al., 2006). The type C cells can give rise to oligodendrocytes or generate immature (“blasts”) neurons called neuroblasts or type A cells in vivo (Doetsch et al., 1999). Together with type B and type C cells, neuroblasts are generally referred as neural progenitor cells (NPCs) and migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB) (Lois and Alvarez-Buylla, 1994), where they differentiate into multiple types of interneurons (Lledo et al., 2008). During an injury, such as stroke (Arvidsson et al., 2002), traumatic brain injury (Ramaswamy et al., 2005), or neurodegenerative diseases (Saha et al., 2012), neuroblasts can migrate towards different areas of the CNS in response to signalling factors. Nevertheless, CNS regeneration process must overcome many obstacles besides NSCs expansion and migration, such as survival, differentiation into specific neural subtypes, and integration into a pre-existing neural network. Despite this capacity of neuroblasts to generate neurons in different CNS areas, the majority of them undergo apoptosis when arriving at a lesion site, resulting in absent or poor regeneration of adult mammalian brain (Arvidsson et al., 2002; Malone et al., 2012; Thored et al., 2006). After a brain injury, soluble factors are released at the lesion site, reaching the SVZ through blood vessels, parenchymal diffusion or cell-cell communication. These factors provide cues that direct neuroblasts to the damaged areas. The chemokine CXCL12 (C-X-C motif ligand 12) – which also regulates homing and maintenance of stem cells in the niches – is among these factors (Kokovay et al., 2010). CXCL12, previously known as SDF-1 (stromal cell-derived factor 1), is a small secreted chemotactic cytokine composed of 67 amino acids. The N-terminus amino acid sequence of CXCL12 (KPVSLSYR, amino acids 1 to 8) (Fig. 1a) is critical for receptor activation and the sequence RFFESHI (amino acids 12 to 18) promotes the initial docking of the chemokine to its receptor CXCR4 (Crump et al., 1997). CXCL12 is abundant and selectively expressed in the developing and mature CNS (Tham et al., 2001), and is secreted by endothelial cells, astrocytes, microglia and neurons (Banisadr et al., 2003). CXCR4 (C-X-C motif receptor 4) is the signalling G protein-coupled receptor of CXCL12, also widely expressed in the CNS (Banisadr et al., 2002). The CXCL12/CXCR4 axis is involved in mobilization, proliferation, migration and differentiation of progenitor cells mainly during development but also in adulthood (Bajetto et al., 1999; Imitola et al., 2004; Itoh et al., 2009; McGrath et al., 1999; Tiveron et al., 2006). Constitutive expression of CXCL12 in the adult CNS is kept at a low level, and is upregulated under injury states, when then CXCL12 enhances the recruitment of neuroblasts from the SVZ neurogenic niche to lesion sites and provides signalling for a potential endogenous stem cell-based repair (for a review see Li et al., 2012).