Animal studies have shown that NSCs generated at the adult hippocampal SGZ form new neurons which integrate in the dentate gyrus (Cameron and Gould, 1994) whereas, NSCs generated at the adult SVZ, form new interneurons which integrate in the olfactory bulb (OB) (Carleton et al., 2003). The adult human SVZ is characterized by a dense ribbon of glial fibrillary acidic protein (GFAP) positive astrocytes that lines the lateral wall of the lateral ventricles. This astrocyte ribbon is highly proliferative and clearly separated from the ependyma by a hypocellular gap layer (Nader Sanai, 2004).

New SVZ-derived neuroblasts which were differentiated from NSCs migrate to the OB through the rostral migratory stream (RMS) in rodents and non-human primates (Craig et al., 1999; Pencea et al., 2001a). In this stream, migrating neuroblasts build elongated chains that are tangentially oriented to the OB, through glial tubes formed by astrocytes (Lois et al., 1996). In humans however, migration of neuroblasts is elusive; studies in the early postnatal brain described a primary corridor connecting the infant SVZ to the OB, and a branching stream that reaches the ventromedial prefrontal cortex (Sanai et al., 2011); studies in the adult human brain indicated the presence of the primary corridor only and described migration of a modest number of neuroblasts (Van Strien et al., 2011).

In MS, neurogenesis possibly occurs at the SVZ leading to generation of new immature neurons in a subgroup of chronic subcortical lesions (Chang et al., 2008). However, neurogenesis in the MS brain is reduced compared to healthy adult brain, leading to lower neuronal supply to the OB which might explain the often reported olfactory deficits in patients (Tepavčević et al., 2011).

In the developing brain gliogenesis follows neurogenesis but persists long after neurogenesis has ceased (Jacobson, 1991). Differentiation of glial progenitor cells results in the formation of astrocytes or oligodendrocytes (Lee et al., 2000). Oligodendrogenesis in adulthood is restricted in and around the SVZ and involves the formation of an intermediate progenitor phenotype, the oligodendrocyte progenitor cell (OPC). OPCs are self-renewing cells that can reside in multiple areas of the adult healthy brain parenchyma until they get activated and differentiated (Menn et al., 2006). Differentiation of OPCs involves expression of specific markers, changes in cellular morphology and extension of endfeet toward the axons for myelination (Compston et al., 1997; Blakemore and Keirstead, 1999; Young et al., 2013).

In MS, loss of axon myelin is often followed by the remyelination of nude axons with new myelin sheaths. Remyelination is a naturally regulated process orchestrated by mature oligodendrocytes (Blakemore and Keirstead, 1999). This process is activated in response to acute demyelination and often leads to formation of shadow plaques, areas of complete repair activity, in otherwise intact white or gray matter. Remyelination activity is high in acute (average 80.7% of all lesions) and persists in chronic progressive MS (average 60% of all lesions). In the WM, remyelination occurs mainly in early inflammatory (Goldschmidt et al., 2009) and chronic active lesions (Patani et al., 2007), the latter being lesions surrounded by a sharp border of activated microglia/macrophages. For remyelination in MS, resident OPCs are recruited and differentiated into mature oligodendrocytes (Gensert and Goldman, 1997; Nait-Oumesmar et al., 1999); moreover, new oligodendrocyte lineage cells are produced by a two to three-fold activation of the adult SVZ in MS (Nait-Oumesmar et al., 2007) and EAE (Picard-Riera et al., 2002; Tepavčević et al., 2011).

In the adult demyelinating brain activated astrocytes and microglia secrete mitogens that induce OPC proliferation, such as the platelet-derived growth factor receptor-2A (PDGF-2A) and fibroblast growth factor-2 (FGF-2) (Franklin and ffrench-Constant, 2008; Clemente et al., 2013). The response of OPCs to mitogens is regulated by the cell cycle regulatory protein p27-Kip1 (Crockett et al., 2005) and the cyclin-dependent kinase 2 (Caillava and Baron-Van Evercooren, 2012). In MS changes in the mitogenic environment induced by alterations in the levels of secreted factors might inhibit proliferation of OPCs (Franklin, 2002). Modulation of growth factor levels such as the FGF-2, was shown to enhance OPC proliferative activity in several in vitro models (Armstrong et al., 2002; Dziembowska et al., 2005).

Animal studies showed that inflammation and demyelination promote migration of OPCs to the lesions (Nait-Oumesmar et al., 1999; Piao et al., 2013). OPCs migrate to early inflammatory and chronic active MS lesions possibly being attracted by FGF-2 expressed by infiltrating macrophages and microglia-derived macrophages (Clemente et al., 2011). In chronic inactive lesions however, formation of the characteristic glial scar composed of hypertrophic astrocytes, limits access of OPCs to the lesion center (Franklin and ffrench-Constant, 2008). Manipulation of chemotactic pathways such as the C-X-C chemokine receptor type 4, pharmacogenetic targets such as the FGF-2 and Anosmin-1, or guidance cues such as semaphorin-3A and 3F, might promote repopulation of MS lesions by OPCs, as it was shown in experimental in vivo or in vitro models for MS and in human MS brain tissue (Williams et al., 2007; Carbajal et al., 2010; Clemente et al., 2011).

Demyelination influences the capacity of OPCs to differentiate by forming a “dysregulated” signaling environment. In chronic MS lesions, OPCs often acquire an immature phenotype which is not permissive for axon remyelination (Wolswijk, 2000). Events that inhibit OPC differentiation are the (1) Excessive accumulation of myelin fragments (Kotter et al., 2006), (2) Deposition of hyaluronan (Sloane et al., 2010), (3) Dysregulation of signaling pathways controlling cell fate, such as the Wnt/β–catenin (Feigenson et al., 2011) and the Notch–Jagged pathway (John et al., 2002; Nakahara et al., 2009) and (4) Changes in levels of growth factors or bone morphogenic proteins (Franklin, 2002; Cheng et al., 2007). Pharmacological manipulation of therapeutic targets such as leucine rich repeat and Ig domain containing 1 (Jepson et al., 2012), retinoic X receptors (Huang et al., 2011), phosphodiesterase-7 (Medina-Rodríguez et al., 2013) and cyclin-dependent kinase 5 (Cdk5) (Luo et al., 2014) or signaling pathways such as the Fyn-Rho-ROCK and protein kinase C (PKC) (Baer et al., 2009) and the Notch/Jagged1 (Blanchard et al., 2013), can be advantageous for the repair of MS lesions.

In the brain of MS patients, mature oligodendrocytes may undergo demyelination thereby losing capacity to myelinate (Wolswijk, 2000). Moreover, demyelinated axons may lose receptivity to myelination by oligodendrocytes due to re-expression of negative regulators, such as the polysialylated neural cell-adhesion molecule (PSA-NCAM) (Charles et al., 2002). These two or other events such as the reported reduction in astrocytic expression of neuregulins (Viehover et al., 2001) or the increased expression of insulin-like growth factor (IGF) binding proteins by oligodendrocytes (Wilczak et al., 2008), might prevent restoration of axon conduction properties in MS lesions. Pharmacological interventions to reverse those events might prove efficient in promoting repair of MS lesions (Lundgaard et al., 2013).

Since sufficient levels of remyelination can repair damaged axons, stimulation of endogenous activity might be beneficial for repair of MS lesions. Besides activation of parenchymal OPCs, generation of new oligodendrocytes for the increase of brain remyelination activity appears a promising perspective for future therapies. This can be achieved with engraftment of transplanted cells or with stimulation of SVZ-derived NSCs by transplanted cells or growth factors to induce differentiation into OPCs.

The confirmed existence of OPCs in the adult brain as well as the increasing understanding of the pathways regulating endogenous remyelination, are the basic reasons why regeneration of oligodendrocytes is a more well investigated approach compared to regeneration of neurons. Replacement of damaged neurons however, is anticipated to offer intriguing possibilities for the rehabilitation of cognitive disturbances in patients with progressive MS. New neurons may repopulate focal sites of degeneration located near the SVZ, such as the OB or the cingulate gyrus, to induce repair, contributing to the re-growth of nerves that have been lost (Figure 1).

Challenges associated with that strategy are linked to the type, density and ability of new neurons to integrate into defined circuits. Acquisition of specific neuronal subtypes is a demanding step for neuronal regeneration of MS lesions since recent evidence indicated heterogeneity and reduced neuropotency in the population of adult SVZ-derived NSCs (Shen et al., 2006). Moreover, the ability of new neurons to functionally mature at the sites of damage is still debated because the sites of lesions are normally non-neurogenic (Obernier et al., 2014). For the expansion of new neurons, and promotion of maturation, specific growth factors can be administered at the SVZ (Table 1). The possibility that new neurons are poorly myelinated due to lack of oligodendrocytes has to be studied. Importantly, the extraordinary proliferation or direction of SVZ-derived NSCs toward neuronal phenotypes other than the ones they were intrinsically committed for might induce unwanted effects linked to tumorigenesis. Monitoring and quantification of NSC activation is required and can be conducted with non-invasive techniques, such as the positron emission tomography (Rueger et al., 2010).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.