Inflammation and degeneration are typical pathological processes occurring in the central nervous system (CNS) of patients with chronic irreversible neurological conditions. They are only apparently separate processes because, as soon as the pathological process becomes chronic, they have the tendency to become strictly interrelated (Martino et al., 2002, 2011; Martino, 2004). Therefore, primary neurodegeneration triggers secondary inflammatory reactions, while primary inflammatory reactions lead to secondary neurodegeneration.

In the last 50 years, it has become clear that the CNS displays intrinsic ‘constitutive’ tissue repair ability to prevent the irreversible tissue damage occurring as a consequence of chronic inflammatory and/or degenerative processes. Several molecular and cellular events sustaining innate brain repair mechanisms have been described. On one hand, humoral and cellular inflammatory components shift their function over time, from a tissue-damaging mode to one promoting tissue repair. Not only pro-inflammatory cytokines may, under certain circumstances, act as anti-inflammatory molecules, but also pro-inflammatory mononuclear cells may promote neuroprotection by secreting neurotrophic factors (Martino et al., 2002). On the other hand, the recruitment of alternative ‘non-damaged’ functioning neuronal pathways – occurring also via axonal sprouting and synaptogenesis – takes place as a consequence of brain damage. Whether or not this process is paralleled by central axon regeneration (i.e. an axon growing back along the distal stump of a crushed or transected nerve to re-innervate its normal target) is still a matter of intense debate (Tuszynski and Steward, 2012). Finally, endogenous neural stem and precursor cells – the self-renewing and multipotent cells of the CNS capable of driving neurogenesis and gliogenesis in adult life – may adapt targeted migration into damaged areas, to promote tissue repair and regeneration via cell replacement and/or the so-called bystander (paracrine) effect, which is due to the capacity of such cells to constitutively secrete neurotrophic and anti-inflammatory molecules (Martino et al., 2011). However, ‘protective’ mechanisms reactive to CNS damage are not strong enough to promote the full recovery of cyto-architecture in most of the chronic inflammatory and degenerative neurological disorders. This evidence supports the ensuing view that irreversible neurodegeneration might be a consequence of the failure of CNS intrinsic repair mechanisms. Thus, it is believed that fostering and/or resetting ‘spontaneous’ regenerative process may lead to more efficacious, and less toxic, therapies.

Given that stem cells are an integral part of the mechanisms sustaining CNS tissue repair processes, strategies that mobilize neural progenitor cells (NPCs) or in vivo transplantation of NPCs might represent promising therapeutic approaches to foster intrinsic repair mechanisms and promote neuroprotection (Martino et al., 2010; Pera and Tam, 2010). In this chapter, we will focus our attention on the self-renewal and differentiation potential and on the recently discovered homeostatic constitutive functions of endogenous NPCs as prerequisites to develop NPC-based transplantation strategies aimed at promoting CNS repair. At the same time, we will also discuss the ability of transplanted NPCs to adapt behaviour and fate in response to the CNS microenvironment and how this behaviour culminates in protection of the CNS from pathogenic signals, the concept of ‘therapeutic plasticity’.

In the adult rodent CNS, neurogenesis continues for the rodent’s entire life mainly in two regions, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (Alvarez-Buylla and Lim, 2004; Zhao et al., 2008). Newly formed adult NPCs of the SGZ migrate short distances and differentiate into dentate granule cells (DGCs) within the dentate granule cell layer (Kallur et al., 2011). These newly formed DGCs migrate into the granule cell layer to become indistinguishable from pre-existing cells and are necessary for modulating and refining the existing neuronal circuits involved in hippocampus-dependent memory processing and behaviour (Imayoshi et al., 2008; Kitamura et al., 2009; Singer et al., 2011). In the rodent, however, SVZ NPCs migrate along the rostral migratory stream (RMS) to the olfactory bulb where they integrate within the granule and glomerular cell layer in order to maintain and reorganize the olfactory bulb system (Imayoshi et al., 2008).

However, recent evidence challenges the sole and exclusive view that the neurogenic CNS areas mainly act as a source of newly formed neurons, able to replace neuronal cells in the hippocampus and in the olfactory bulb (Imayoshi et al., 2008). As a matter of fact, adult NPCs residing within germinal niches might exert other ‘non-neurogenic’ homeostatic regulatory functions alternative to cell replacement during either a healthy state or pathology.

Apart from a recent report showing that neurogenesis in the SGZ exerts an antidepressant activity by regulating (via glucocorticoid release buffering) the hypothalamus–pituitary axis (Snyder et al., 2011), evidence collected so far suggests that SVZ represents the more ‘strategic’ area where NPCs might exert a homeostatic role in addition to neurogenesis. This is because, on one side, these cells are in communication with two different microenvironments, tightly apposing blood vessels and in contact with the cerebrospinal fluid (CSF) through apical processes (Sawamoto et al., 2006; Rolls et al., 2007; Mirzadeh et al., 2008; Tavazoie et al., 2008). On the other side, the SVZ is very close to crucial areas of the midbrain (e.g. the basal ganglia and striatal structures) containing GABAergic neurons capable of efficiently regulating and modulating interconnections between several cortical and sub-cortical brain areas (Koos and Tepper, 1999).

As already anticipated, CNS pathology results in loss of either neural or glial cells and disrupts the cyto-architecture of the tissue that is defined during development, when neurons and glia precociously acquire specific positional identities (Hochstim et al., 2008; Sauka-Spengler and Bronner-Fraser, 2008) and their integrity is required for correct CNS functioning (Eroglu and Barres, 2010). Therefore, cell replacement strategies would represent an ideal therapeutic approach for CNS disorders, owing to the fact that it not only aims at substituting dead cells with newly differentiated ones but also promotes functional integration into neural circuits of newly formed cells (Ingber and Levin, 2007; Poss, 2010).

With this in mind, several cell replacement–based therapeutic strategies have been established. The results, obtained so far, reveal that this approach does represent a rational and realistic therapeutic strategy for only a restricted category of neurological disorders, and the success of this strategy is very much dependent on the cell type to be substituted and on the CNS region damaged. Cell replacement is efficacious in disorders in which degeneration is caused by either intrinsic cellular defects of, or extrinsic factors that are no longer active in, a specific cell population residing within a discrete CNS area, but where the general architecture of the tissue is maintained. In animal models of Parkinson’s disease (PD), dopaminergic neuronal precursors – derived from different animal species (Dunnett et al., 1987; Wictorin et al., 1992; Isacson and Deacon, 1996; Starr et al., 1999) and cell sources (Dunnett et al., 1987; Shim et al., 2007; Wernig et al., 2008) – can survive, re-innervate the striatum and ameliorate clinical outcome, when grafted either in the substantia nigra or in the striatum (Gaillard and Jaber, 2011). In animal models of genetically induced dysmyelination and/or hypomyelination (i.e. shiverer mouse) (Ben-Hur et al., 2005; Duncan et al., 2011) or chemically induced demyelination (Blakemore and Franklin, 2008), intraparenchymal transplantation of many different myelinating cell types extensively remyelinates denuded axons (Windrem et al., 2004; Buchet et al., 2011; Sim et al., 2011).

In contrast, cell replacement has been only partially satisfactory in a persistently unfavourable environment, where different cell sub-populations in different CNS areas are affected and where the tissue architecture is altered, such as in stroke, spinal cord injury (SCI), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) (Chen and Palmer, 2008). In stroke and SCI animal models, NPCs from multiple sources have been demonstrated to functionally integrate into the host neural circuits and differentiate into neurons (Kelly et al., 2004; Cummings et al., 2005; Buhnemann et al., 2006; Yan et al., 2007; Daadi et al., 2009; Braz et al., 2012). Likewise, in animal models of MS and SCI, both NPC and glial-restricted progenitors can remyelinate injured axons (Archer et al., 1997; Pluchino et al., 2003; Keirstead et al., 2005; Lee et al., 2009; Sharp et al., 2010; Yang et al., 2010). However, it still remains to be demonstrated if this cell replacement mechanism is the sole mechanism functionally accountable for the clinical amelioration (Dubois-Dalcq et al., 2005; Pluchino et al., 2005; Bacigaluppi et al., 2009b; Sahni and Kessler, 2010). Other mechanisms that will be discussed in this chapter (e.g. the bystander effect) may also contribute to the therapeutic effect observed upon NPC transplantation.

Another issue is the degree of complexity of the tissue patterning that transplanted cells need to restore. PD and focal demyelination are diseases in which specific cell types are necessary to re-establish appropriate interactions at the cellular level; in PD dopaminergic circuits should be restored within the striatal region, while in demyelinating disorders a properly functioning saltatory conduction should be achieved via efficient remyelination. However, very few studies have been able to demonstrate that cell transplantation might lead to the generation of long-distance connections in diseases in which degeneration impairs multiple widespread afferent–efferent connections, such as ALS and other motor neuron disorders (Verstraete et al., 2011), Huntington’s disease (HD) (Wolf et al., 2008) or spinocerebellar ataxias (Di Giorgio et al., 2011; Yohn et al., 2008; Solodkin et al., 2011; Lepore et al., 2011).

The last issue to be considered when designing therapies aimed at promoting cell replacement is the timing of cell transplantation. In primary neurodegeneration, transplantation should be performed at the beginning of the neurodegenerative process in order to limit the cascade of events leading to the degeneration of other cell populations. Data clearly show that transplanted NPCs acquire an appropriate terminally differentiated fate and integrate functionally in the host tissue (Goldman, 2005; Breysse et al., 2007; Lindvall and Kokaia, 2010), an event particularly evident when there is a partial preservation of the neuronal circuits’ cyto-architecture (Shihabuddin et al., 1996). On the other hand, while early transplantation is recommended in degenerative diseases, in primary inflammatory disorders (e.g. stroke, SCI and MS) transplantation aimed at cell replacement would be useful only during the post-acute phase of the disease (Karimi-Abdolrezaee et al., 2006; Bacigaluppi et al., 2009b) when the inflammatory phase is limited. It is now clear that the immune milieu can influence, either detrimentally or protectively, the fate of transplanted cells (Carpentier and Palmer, 2009; Deverman and Patterson, 2009; Ransohoff, 2009; Giannakopoulou et al., 2011; Muja et al., 2011; Kokaia et al., 2012).