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Keywords:

  • adult neurogenesis;
  • Musashi-1;
  • neural stem cells;
  • reactive astrocytes

Abstract

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

Recent advances in developmental and stem cell biology have made regeneration-based therapies feasible as therapeutic strategies for patients with damaged central nervous systems (CNSs), including those with spinal cord injuries, Parkinson disease, or stroke. These strategies can be classified into two approaches: (i) the replenishment of lost neural cells and (ii) the induction of axonal regeneration. The first approach includes the activation of endogenous neural stem cells (NSCs) in the adult CNS and cell transplantation therapy. Endogenous NSCs have been shown to give rise to new neurons after insults, including ischemia, have been sustained; this form of neurogenesis followed by the migration and functional maturation of neuronal cells, as well as the responses of glial cells and the vascular system play crucial roles in endogenous repair mechanisms in damaged CNS tissue. In this review, we will summarize the recent advances in regeneration-based therapeutic approaches using endogenous NSCs, including the results of our own collaborative groups.

Abbreviations used:
ChEI

acetylcholinesterase inhibitor

DG

dentate gyrus

EGF

epidermal growth factor

GFAP

glial fibrillary acidic protein

GFP

green fluorescent protein

MCAO

middle cerebral artery occlusion

NSC

neural stem cell

OB

olfactory bulb

OLG

Oligodendrocyte

OPC

oligodendrocyte progenitor cell

SCI

spinal cord injury

SGZ

subgranular zone

SVZ

subventricular zones

TA

transit-amplifying

As Cajal’s dogma (Ramón y Cajal 1928) states, the regenerative capacity of the CNS is extremely limited. The mammalian CNS is a complex biologic system in terms of its cellular architectures, neural networks, and functional localization and integration. Thus, injuries to this system as a result of various insults, including [stroke, spinal cord injury (SCI), Parkinson disease, and Alzheimer disease], result in various functional deficits and abnormalities. Nevertheless, rapid progress in developmental and stem cell biology in recent years has led to an increasing interest in regeneration-based treatment strategies for damaged CNS tissue. These novel tactics are based on the recapitulation of the normal developmental process, and include (i) the replenishment of lost neural cells, (ii) the induction of axonal regeneration and (iii) functional recovery and refinement (Okano 2002a,b, 2003, 2006). Regarding cellular replenishment, stem cell-based therapies – including the activation of endogenous neural stem cells (NSCs) in the adult CNS and cell transplantation therapies (reviewed by Lindvall et al. 2004) – are promising. In this review article, we will summarize recent investigations into such strategies, including our own works.

NSCs and neurogenesis in the adult mammalian CNS

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

Neural stem cells are tissue-specific somatic stem cells that are present within the CNS. They are characterized by their multi-lineage potential and self-renewal activity (Okano 2002a,b, 2006). In the adult mammalian CNS, the major population of endogenous NSCs is located in the periventricular area throughout the neuroaxis from the forebrain to the spinal cord (Temple and Alvarez-Buylla 1999). Previously, in collaboration with Dr Steve Goldman’s group in the US, we were able to identify putative neural stem/progenitor cells in the adult human brain (Pincus et al. 1998) using an RNA-binding protein, Musashi-1, as a marker (Kaneko et al. 2000; Sakakibara et al. 1996; Sakakibara and Okano 1997; reviewed by Okano et al. 2002, 2005). The putative neural stem/progenitor cells were prospectively isolated from surgically excised adult human brain tissues (Roy et al. 2000a,b) using neural stem/progenitor cell-selective green fluorescent protein (GFP)-reporter genes, including the nestin 2nd intronic enhancer-driven GFP (nestin-GFP) (Kawaguchi et al. 2001). The isolated cells were cultured in the presence of Fibroblast Growth Factor-2 and gave rise to functionally active neurons in vitro (Roy et al. 2000a,b). These findings indicated that adult human brains did contain NSCs or NSC-like cells in the periventricular area (reviewed by Okano 2006).

In adult animals, the de novo production of new neurons (neurogenesis) under physiological conditions occurs only in the subventricular zones (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). In terms of glial fibrillary acidic protein (GFAP) expression, NSCs in the SVZ have the characteristics of astrocytes (Doetsch et al. 1999) (hereafter referred to as SVZ astrocytes to distinguish them from astrocytes in other regions). In some reports, SVZ astrocytes have also been defined as type B cells, based on their morphology (Doetsch et al. 1997). NSCs proliferate and produce transit-amplifying cells (TA cells). TA cells rapidly proliferate and differentiate into neuroblasts. These neuroblasts migrate to the olfactory bulb (OB), where their final differentiation into interneurons takes place. Each progenitor type in the SVZ can be distinguished by its expression pattern of molecular markers (Fig. 1) (Ming and Song 2005; Sakaguchi et al. 2006, 2007). In both the SVZ and the SGZ, adult neurogenesis occurring under physiologic conditions is likely to have various physiological significances (Kempermann 2006a; Kempermann and Gage 1999). When the brain suffers an insult (such as brain ischemia), newly generated neurons appear in the striatum and cerebral cortex (insult-induced neurogenesis) (Arvidsson et al. 2002; Liu et al. 1998; Tonchev et al. 2005); thus, treatment using intrinsic NSCs may be feasible, particularly in cases with cerebral infarction. Insult-induced neurogenesis comprises the following three processes: (i) the activation of endogenous NSCs; (ii) the division of TA cells and the migration of neuroblasts; (iii) the survival and maturation of the newly generated neurons at the site of injury and their inclusion in the existing neural circuitry. To establish new therapeutic methods using endogenous NSCs, the detailed mechanisms involved at each of these steps must be clarified.

image

Figure 1.  Marker expression pattern for each stage of neural cell differentiation during in adult neurogenesis in the subventricular zone. Neural stem cells (NSCs; type B cells) slowly divide to generate transit-amplifying cells (TA cells; type C cells), which proliferate rapidly and produce neuroblasts (type A cells). Neuroblasts migrate through the rostral migratory stream into the olfactory bulb where they differentiate into neurons (N).

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Activation of endogenous NSCs

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

Previously, Liu et al. (1998) used 5-bromodeoxyuridine immunohistochemistry in an adult gerbil model for transient global ischemia (induced by 10 min of bilateral common carotid artery occlusion) and reported that cell birth in the SGZ of the hippocampal DG had increased by 12 fold at 1–2 weeks after insult. Newborn cells with a neuronal phenotype were first observed 26 days after ischemia; these cells survived for at least 7 months, were located only in the granule cell layer, and comprised ∼60% of the BrdU-labeled cells in the granule cell layer at 6 weeks after ischemia. Since this initial study, many others have conducted experiments using models for transient ischemia of the forebrain and middle cerebral artery occlusion (MCAO) and have reported that these stem/progenitor cells are activated in the SVZ and SGZ after cerebral ischemia. MCAO-induced ischemic stroke has been shown to trigger an increase in cell proliferation and neurogenesis in rat SVZ (Arvidsson et al. 2002). Furthermore, the migration of newly formed neuroblasts into the damaged striatum, a region where neurogenesis does not occur, was observed in intact rat brain (Arvidsson et al. 2002). Surprisingly, the generation of striatal neuroblasts was sustained for at least 4 months after the stroke insult in adult rats, indicating that endogenous neural stem/progenitor cells continuously supplied the injured adult brain with new neurons (Thored et al. 2006). Recently, Liu et al. (2007) conducted a comprehensive study on gene expression patterns in the SVZ using a microarray technique and samples from a transient MCAO model. They reported that in the SVZ on the infarcted side, the Wnt and Notch pathways involved in the maintenance and self-renewal proliferation of various stem cells; (Reya et al. 2001) and the Sox-family proteins (a group of related transcription factors that are highly expressed in various stem cells) are involved in the activation of NSCs.

To identify other regulators involved in the activation of adult NSCs, we screened for factors promoting the proliferation of neural stem/progenitor cells in vitro using a recently developed proteomics technique, the ProteinChip system (Fung et al. 2001). Using this screening process, we identified a soluble carbohydrate-binding protein, Galectin-1, as a candidate molecule involved in the activation of neural stem/progenitor cells (Sakaguchi et al. 2006). In the SVZ of adult mouse brain, Galectin-1 is expressed in GFAP-positive SVZ astrocytes (type B cells), i.e. slowly dividing NSCs located in this niche. Based on results from the intraventricular infusion of a recombinant protein and phenotypic analyses of knockout mice, we demonstrated that Galectin-1 is an endogenous factor that promotes the proliferation of NSCs in adult brain. We also found that the carbohydrate-binding activity of Galectin-1 is essential for its promotion of adult neural stem/progenitor cell proliferation. We hypothesized that Galectin-1 may mediate the interaction between NSCs and the extracellular matrix in the SVZ, creating a stem cell niche, through its carbohydrate binding activity (Fig. 2). To date, the functional significance of the interaction between endogenous lectins and their target glycans expressed on adult NSCs has not been extensively clarified in vivo. Considering that most membrane-bound proteins are glycosylated, understanding the effect of Galectin-1 on the behavior of neural stem/progenitor cells should contribute to our understanding of the importance of lectin-glycan interactions in the regulation of stem cells (Sakaguchi et al. 2007).

image

Figure 2.  A possible mechanism of Galectin-1 in the proliferation of neural stem cells (NSCs) in the adult subventricular zone. For this activity, the glycan-binding ability of Galectin-1 in the extracellular matrix is required. Thus, Galectin-1 may mediate the interaction of NSCs and the extracellular matrix through its divalent glycan-binding activity. Currently, neither the sequence of the glycan nor its counter-receptor (the carrier molecule of the glycan) in the subventricular zone have has been clarified. Other mechanisms are also possible (i.e., bringing the two counter-receptors expressed by NSCs closer on their membranes).

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Recently, the group of Drs Fred Gage and Gerald Kempermann reported a considerable difference in the degree of adult neurogenesis in the hippocampi of inbred mouse strains (Kempermann et al. 2006b). In their study, a large-scale quantitative analysis of gene expression patterns in recombinant inbred strains indicated that Musashi-1, an RNA-binding protein mentioned above, was important for the maintenance of NSCs in the SGZ of the adult hippocampal DG. Musashi-1 is expressed in neural stem/progenitor cells from embryonic (Sakakibara et al. 1996) to adult stages (Sakakibara and Okano 1997) in mammalian brain tissue. We have found that Musashi-1 is required for the self-renewal of NSCs by augmenting Notch signaling through the translational repression of m-Numb mRNA (Imai et al. 2001; Sakakibara et al. 2002; reviewed by Okano et al. 2002; Okano 2006). It would be interesting to examine whether Musashi-1 activity is also involved in the regulation of adult hippocampal neurogenesis and insult-induced neurogenesis. Previous reports have indicated that Musashi-1 expression is up-regulated after ischemic insults (Yagita et al. 2001, 2002). We are currently examining how ischemic insults induce the up-regulation of Musashi-1 and the possible involvement of Musashi-1 in the insult-induced activation of neural stem/progenitor cells and neurogenesis.

Proliferation of TA cells and migration of neuroblasts

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

The proliferation of TA cells is another important factor involved in the robustness of adult neurogenesis. We recently reported that the epidermal growth factor (EGF) pathway is involved in this process (Ninomiya et al. 2006). An infusion of EGF increased the number of regenerated neurons in the striatum of an MCAO model of cerebral ischemia. However, the types of cells that are stimulated to proliferate or differentiate in the SVZ after EGF infusion remain unknown. We found that cerebral ischemia increases the number of EGF receptor-positive TA cells in the SVZ. An infusion of EGF into ischemic brain caused the number of TA cells to increase and the number of neuroblasts to decrease. Six days after the discontinuation of EGF infusion, however, the number of neuroblasts in both the striatum and the SVZ significantly increased, suggesting that the replacement of neurons in the injured striatum can be enhanced by an EGF-induced expansion of TA cells in the SVZ (Ninomiya et al. 2006). Whether the EGF-pathway is actually required for the expansion of TA cells in the SVZ would be interesting to examine.

After cerebral ischemia, newly generated neurons can be found in ‘non-neurogenic sites’, such as the striatum and cerebral cortex, where neurogenic processes do not normally occur in adult animals. This observation can be interpreted in two ways: (i) the neurons were generated in the vicinity of the SVZ and migrated into these ‘non-neurogenic sites’; or (ii) the generation of new neurons was ectopically induced in ‘non-neurogenic sites’ as a result of the ischemic insult. Magavi et al. (2000) observed the development of newly divided mature neurons at a site where the neurons of the cerebral cortex had been destroyed. They reported that these cells were supplied from two sources – neuronal precursor cells in the cerebral cortex and the SVZ. Previous reports on MCAO-induced neurogenesis by Parent et al. (2002) and Arvidsson et al. (2002) preferred the first migration model. Interestingly, Arvidsson et al. (2002) showed that stroke, caused by transient MCAO in adult rats, led to a marked increase in cell proliferation in the SVZ and that these stroke-generated new neurons migrated into the severely damaged area of the striatum. Regarding the second ectopic neurogenesis model, one possible source is the striatal parenchyma, as this region may also contain latent stem/progenitor cells that can be activated and become neurogenic when stimulated by neurotrophic factors (Palmer et al. 1995; Pencea et al. 2001).

Recently, we used region- and cell type-specific cell labeling and long-term tracing techniques utilizing a Cre-loxP system to identify ectopic newly generated neurons in the striatum after MCAO (Yamashita et al. 2006). Our results demonstrated that the putative NSCs at the SVZ (SVZ astrocytes) were the principal source of the neuroblasts, which formed chain-like structures and migrated laterally toward the injured striatal regions, then differentiated into mature neurons. Interestingly, these chains of neuroblasts were closely associated with thin astrocytic processes and blood vessels, suggesting that the blood vessels may act as a scaffold for neuroblast migration to injured striatal regions (Yamashita et al. 2006). Notably, this type of directional migration from the SVZ to the striatum never occurs in intact brain. In addition to the potential contribution of blood vessels as scaffolding, a diffusible chemoattractant is likely to be involved. Recently, the directed migration of new neurons towards areas of ischemic damage was shown to be regulated by chemoattraction through stromal cell-derived factor-1alpha and its receptor chemokine (CXC motif) receptor 4 (Thored et al. 2006).

In adult intact brain, neuroblasts born in the SVZ migrate from the walls of the lateral ventricles to the OB. Recently, Sawamoto et al. (2006) showed that a chemorepellant known as Slit protein (produced at the choroid plexus) and its gradient (generated by the flow of cerebrospinal fluid) play crucial roles in the directional migration of neuroblasts. It would be interesting to examine the roles of the Slit protein gradient on ischemia-induced neuroblast migration.

As a result of the findings described above, the signaling mechanisms involved in the proliferation of TA cells and the subsequent migration of neuroblasts have been at least partially elucidated. These findings may well facilitate the design of drugs as therapeutic reagents to enhance and properly regulate the regenerative process after an insult has been sustained.

Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

Once the neuronal precursors reach the site of injury, they must differentiate into neurons, form a neural circuit network, and restore function for the ultimate goal of regenerative medicine to be achieved. According to Arvidsson et al. (2002), however, the percentage of neurons that traveled to the striatum and were able to mature accounted for only 0.2% of the neurons that had been lost in an MCAO model, indicating that further research is needed to enhance the survival, and/or maturation of newly generated neurons.

In addition to its roles in learning and memory, the basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis in this region. We recently reported that basal forebrain cholinergic input is strongly associated with the survival of newly generated neurons. Cholinergic fibers were shown to innervate both the OB and the DG, where neuronal progenitor cells and immature neurons express various subtypes of acetylcholine receptors (Kaneko et al. 2006). We found that the administration of donepezil, a potent and selective acetylcholinesterase inhibitor (ChEI) that improves cognitive impairment in patients with Alzheimer disease, significantly enhanced the survival of newborn neurons, but not the proliferation of neural stem/progenitor cells, in the SGZ or the SVZ of normal mice. Another group recently reported that ChEI-treatment enhanced the survival of newborn cells in the DG via cAMP response element binding protein-signaling without affecting neural stem/progenitor cell proliferation and neuronal differentiation (Kotani et al. 2006). Notably, our results showed that ChEI-treatment reversed chronic stress-induced reductions in adult neurogenesis, indicating that the therapeutic effects of ChEI support insult-induced neurogenesis (Kaneko et al. 2006).

Endogenous repair mechanisms other than adult neurogenesis

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

Endogenous repair mechanisms for damaged CNS tissue are not restricted to adult neurogenesis. Research on glial cells and the vascular system that surrounds these cells should also be simultaneously conducted.

Oligodendrocytes (OLGs), myelin-forming glial cells in the CNS, are quite vulnerable to ischemic stress, resulting in the early loss of myelin (Dewar et al. 2003; Shibata et al. 2000). On the other hand, oligodendrocyte progenitor cells (OPCs) have been shown to exist widely throughout mature brain. Recently, increasing attention has been paid to OPCs in terms of CNS repair, because they are found not only during development, but also remain abundant throughout the adult brain (Levine and Reynolds 1999). A previous study indicated that OPCs in the peri-infarct gray matter exhibited enlarged cell bodies with hypertrophied processes during the post-ischemic reperfusion period in rat brain (Tanaka et al. 2001). Furthermore, Tanaka et al. (2003) reported that OPC activation and proliferation are induced around infarction foci after focal ischemia in the rat brain (90-minute MCAO model, followed by a reperfusion period of up to 2 weeks). In their second report, Tanaka et al. suggested that the up-regulation of OPCs may contribute to the replenishment of OLGs and subsequent remyelination in the peri-infarct area after an ischemic insult. Relevant to this finding, a previous report had shown that remyelinating cells were locally recruited during the repair of demyelinated areas in adult rat spinal cord (Franklin et al. 1997). In Franklin et al.’s study, remyelinating cells were not recruited into the areas of demyelination from distances greater than 2 mm, implying that most of the remyelinating cells were locally generated (Franklin et al. 1997), presumably from OPCs. Recently, type B cells in the SVZ have also been shown to generate a small number of non-myelinating NG2-positive OPCs and mature myelinating OLGs. Some type B cells and a small subpopulation of active TA cells expressed OLG lineage transcription factor 2 (Olig2), suggesting that OLG differentiation in the SVZ begins at an early stage during the cell lineage (Menn et al. 2006). Notably, SVZ-derived OLGs are likely to participate in repair mechanisms. The number of OLGs derived from type B cells in vivo increased fourfold after a demyelinating lesion in the corpus callosum, indicating that SVZ type B cells participate in myelin repair in the adult brain. Collectively, SVZ type B cells have been regarded as progenitors of OLGs in normal and injured adult brains (Menn et al. 2006).

The roles of reactive astrocytes in the repair of damaged CNS tissue have been controversial. Reactive astrocytes are thought to produce chondroitin sulfate proteoglycan, which inhibits axonal regeneration, thereby exerting a detrimental effect on CNS repair. However, we recently found that reactive astrocytes also have beneficial effects on repair during the subacute phase of SCI (Okada et al. 2006). Reactive astrocytes were shown to play a crucial role in wound healing and functional recovery during the subacute phase of SCI, before the completion of glial scar formation. During the subacute phase of SCI (from 1 to 2 weeks after SCI), astrocytes surrounding the lesion underwent characteristic changes involving hypertrophy, process extension, and the increased expression of intermediate filaments like GFAP and Nestin within 7 days of SCI; these changes are characteristic of ‘reactive astrocytes.’ Notably, these astrocytes eventually migrated centripetally to the lesion epicenter and gradually compacted the CD11b+ inflammatory cells, contracting the lesion area up until 14 days after SCI. We found that this migratory response of the astrocytes requires the activity of Stat3, which is a principal mediator in a variety of biologic processes including cancer progression, wound healing and the movement of various types of cells (Hirano et al. 2000). This finding also raised Stat3 signaling and reactive astrocytes as potential new therapeutic targets for the treatment of traumatic injury in the CNS (Okada et al. 2006).

The roles of the vascular system in CNS-repair have also attracted much attention in terms of the ‘angiogenic niche model’ of adult neurogenesis (Palmer et al. 2000) and our recent results indicating the potential roles of blood vessels as scaffolds for neuroblast migration in ischemic brain (Yamashita et al. 2006). Palmer et al. (2000) suggested that neurogenesis was intimately associated with the process of active vascular recruitment and subsequent remodeling. Accordingly, they proposed that adult neurogenesis occurred within an angiogenic niche, which may provide a novel interface where mesenchyme-derived cells and circulating factors influence plasticity in the adult CNS. Interestingly, Shen et al. (2004) showed that vascular endothelial cells released soluble factors that stimulated the self-renewal of NSCs, suggesting vascular endothelial cells to be a critical component of the NSC-niche. Angiogenesis is known to occur following cerebral infarction. Regarding the significance of cerebral infarction-induced angiogenesis, Hayashi et al. (2003) conducted a microarray analysis of the changes in the expression of angiogenesis-related genes following infarction in an MCAO model. Their results demonstrated that the expression of several angiogenesis-related genes was regulated in an orchestrated fashion in the brain after ischemia, and they suggested that this phenomenon should be taken into account when examining therapeutic angiogenesis following stroke.

Conclusion and perspectives

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

Although the enhancement of adult neurogenesis could be a potentially feasible therapeutic strategy for various types of brain damage, recent studies have indicated that excess adult neurogenesis can be as detrimental as a deficit. Accordingly, Scharfman and Hen (2007) have claimed that the clinical relevance of enhancing neurogenesis needs to be reconsidered in some cases. Thus, we must accept that our knowledge regarding the functions of newly generated neurons in vivo is still somewhat immature. Answering the question of the functional significance of adult neurogenesis will open a new era of brain science in which stem cell biology and cognitive neuroscience are connected. Enhancing neurogenesis has also been shown not to be beneficial with regard to the pathology of epilepsy (Scharfman 2004; Scharfman and Hen 2007). The inappropriate migration, differentiation, and integration of numerous new neurons in the hippocampal DG of animal models for temporal lobe epilepsy are likely to result in severe prolonged seizures (status epilepticus). Thus, in this context, elucidating the underlying mechanisms responsible for the migration of neuroblasts, the survival of newly generated neurons, and their functional maturation and subsequent inclusion in neural circuitry, in addition to the mechanisms underlying neurogenesis, is obviously crucial.

Importantly, adult neurogenesis is not the only self-repair mechanism for damaged CNS tissue. Similar to the situation in intact CNS, appropriate interactions among neurons, glial cells and vascular systems are crucial for CNS repair. As described in this mini-review, the glial response and angiogenesis are active participants in these repair mechanisms. Elucidating and then controlling the appropriate regulatory mechanisms in these cells will be a major target in the development of regeneration-based therapeutic strategies for damaged CNS tissue.

Acknowledgements

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References

We are grateful to the members of the Okano Laboratory for their comments regarding this manuscript. This work was supported by a grant from the Solution-Oriented Research for Science and Technology (SORST) program of the Japan Science and Technology Agency (JST) and from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

References

  1. Top of page
  2. Abstract
  3. NSCs and neurogenesis in the adult mammalian CNS
  4. Activation of endogenous NSCs
  5. Proliferation of TA cells and migration of neuroblasts
  6. Survival and maturation of newly generated neurons at the site of injury and the construction of new neuronal circuits
  7. Endogenous repair mechanisms other than adult neurogenesis
  8. Conclusion and perspectives
  9. Acknowledgements
  10. References
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