The concept that the adult mammalian brain contains populations of resident neural stem/progenitor cells (hereafter collectively referred to as NSPCs) was generally accepted two decades ago (Reynolds and Weiss, 1992
; Richards et al., 1992
), although first shown by Altman and Das in 1965 (Altman and Das, 1965
). Adult neurogenesis occurs primarily in two neurogenic regions in the brain, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. To produce new neurons a NSPC must go through a process of proliferation, migration, differentiation, and integration to become a productive member of existing circuitry in the brain. Under normal physiological conditions adult NSPCs predominantly produce neurons, in particular interneurons in the olfactory bulb (OB) for SVZ-derived cells and dentate gyrus granule cell neurons for SGZ-derived cells. Following neural damage, however, SVZ-derived cells have the capacity to respond to the insult and produce neurons as well as astrocytes and oligodendrocytes. Harnessing this ability of NSPCs to produce new neuronal and glial cells as a means to replace cells damaged or lost following neural injury or disease to promote neural repair has been the focus of a substantial body of research. There are four main areas in the life cycle of a NSPC that can be targeted to try to enhance neural repair, namely proliferation, migration, differentiation (and specific cell type generation), and survival/integration. However, the field is full of conflicting reports on the benefit and ability of NSPCs to recover function following a range of injuries and diseases. While many labs have reported an increase in proliferation of neuroblasts and even migration to injured areas, a large part of the problem may lie in the failure of newly generated neurons to integrate into existing neural circuitry and survive past 4 weeks or so after their generation. Augmentation of all steps of the process of neurogenesis would ideally lead to an increased benefit following injury, but ultimately the cells must integrate and survive to have a functional benefit.
This review will cover some of the main factors known to be involved in neurogenesis and gliogenesis in the adult CNS and in particular those that have been shown to play a role in neural repair. It will also explore how inflammatory mediators and other injury-related factors may modify the NSPC response to neural damage. We will not undertake a comprehensive review of factors regulating neurogenesis and gliogenesis in the normal developing or adult brain, as there have been several recent and comprehensive reviews covering this area (e.g., Guillemot, 2007
; Ming and Song, 2011
; Faigle and Song, 2012
). Rather, we will highlight factors that play a role in regulation of normal adult NSPC function and which have been shown to be modulated to enhance repair following neural damage. Table summarizes the factors discussed, which NSPC populations are affected (SVZ or SGZ), the type of neural injury, if any and the NSPC function affected. Figure depicts the effects of extrinsic factors on the SVZ-derived NPC response to injury.
Extrinsic factors affecting SVZ and SGZ NSPC responses under basal conditions and following neural damage.
Figure 1 Factors that when administered to the brain following neural damage regulate neural precursor cell responses. (A) Basal, non-damage conditions. Inset (A.1) depicts the two main neurogenic regions of the adult rodent brain, the subventricular zone (SVZ) (more ...)
NSPC fate: normal neurogenic niches vs. the injured CNS environment
Although the bulk of neurogenesis and gliogenesis occurs during embryonic and early postnatal development, NSPCs continue to produce neural cells in the adult brain. Importantly for the purpose of harnessing adult NSPCs for neural repair, unlike during development, the vast majority of adult-derived cells are fated to a neuronal lineage, with a much smaller percent differentiating into oligodendrocytes in the normal adult brain. In general, the diversity of cell types and neuronal subtypes that can be spontaneously generated by adult NSPCs is substantially limited compared to embryonic cells. This is probably largely due to a less permissive adult environment rather than a constitutive feature of the NSPCs themselves, as under appropriate conditions, such as in neurospheres in vitro
(Reynolds and Weiss, 1992
) or following ablation of neuronal populations without inflammatory system activation (Magavi et al., 2000
), the ability of adult NSPCs to produce different neural cell types has been demonstrated. The more restricted fate of adult NSPCs in the normal adult CNS reflects the relative paucity of growth and neurotrophic factors compared to during development. The presence of inhibitory/attractive substrates, such as in the RMS, to constrain migratory routes and the lack of available space in the adult circuitry to allow integration of newborn cells, in general restricts normal NSPC function to neurogenic regions and currently limits the ability of endogenous NSPCs to replace specific neuronal or glial types in different regions in the CNS.
To further complicate matters, the injured adult CNS is an entirely different environment to the normal adult neurogenic niche or the developing nervous system, with substantial influence on NSPC function that in some instances appear to override the normal program of NSPC fate. This is particularly the case for SVZ NSPCs, which, as detailed further below, can be induced away from their normal migratory route to the OB toward the site of neural damage, a process largely induced by inflammatory mediators. After successful migration to the correct location, new neuroblasts must differentiate into the proper phenotype of neuron and integrate into local circuitry. The local circuitry to be repaired will depend on the type of damage, be it ischemic, traumatically injured or neurodegenerative, with some common factors and others specific to the site and type of damage. Effects of exogenous factors have been variably examined in each of the above types of neural damage and are described below for the relevant factors.
The majority of research on ectopic migration and neural differentiation of SVZ-derived NSPCs following neural damage has been performed by use of ischemia models and has demonstrated that cells do indeed reach the injured parenchyma (Arvidsson et al., 2002
; Parent et al., 2002
; Jin et al., 2003
; Sundholm-Peters et al., 2005
; Ohab et al., 2006
; Yamashita et al., 2006
; Cayre et al., 2009
; Young et al., 2011
). It appears that the cells in general no longer migrate in a chain formation and carry on individually, with some reports describing an increase in progenitor numbers without an effect on numbers of cells in the RMS (Zhang et al., 2001b
), while others report that the response to injury is at the expense of the RMS population (Jin et al., 2003
; Goings et al., 2004
). This change in migration is the direct result of chemoattractive cues expressed from the injury site. As detailed further below, chemokines and their receptors can attract neuroblasts from the RMS. For example, Stromal cell-derived factor-1/CXCL12 and its receptor CXCR4 are upregulated at the injury site (Imitola et al., 2004
; Robin et al., 2006
) and expression of several other chemokines and their receptors are upregulated on adult NSPCs by inflammatory cytokines, such as IFNγ and TNFα (Turbic et al., 2011
In general ischemia models have demonstrated production of new neurons from the SVZ in damaged cortex or striatum, while injury of the cortex usually promotes the generation of astrocytes and microglia/macrophages at the site of injury, with few or no new neurons produced (Ramaswamy et al., 2005
; Richardson et al., 2007
; Kreuzberg et al., 2010
; Blizzard et al., 2011
; Zhang et al., 2011
). Neurodegenerative disease models, such as Parkinson's disease (PD) models, have also demonstrated migration of SVZ NPCs to the site of damage, with production of neurons in some cases but not others (Cooper and Isacson, 2004
; Kadota et al., 2009
; Jing et al., 2012
). The production of astrocytes and oligodendrocytes near the injury site may be a result of expression of repressors of neuronal fate (Kernie et al., 2001
; Shear et al., 2004
; Buffo et al., 2005
). Further, as detailed below, administration of a variety of factors promotes neurogenesis and/or gliogenesis in these normally non-neurogenic sites. The SVZ-derived NSPC response and the new cells they produce is quite variable, depending on injury type, region of neural damage, species and likely a range of other factors that remain to be defined.
There is little/no evidence that SGZ hippocampal NSPCs can migrate away from their normal GCL fate; however they do respond to neural damage (Dash et al., 2001
; Chirumamilla et al., 2002
), even if the hippocampus is not directly affected by damage, such as in cortical impact models (Kernie et al., 2001
). This leads to alterations in neurogenesis that can produce altered cognition and/or effects on memory and anxiety. Little is currently known about how this neurogenesis is altered, but will be touched on below.