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Journal of Neuroscience Research 76:223–231 (2004) Endogenous Adult Neural Stem Cells: Limits and Potential To Repair the Injured Central Nervous System Nathalie Picard-Riera, Brahim Nait-Oumesmar, and Anne Baron-Van Evercooren* Institut National de la Santé et de la Recherche Médicale, U546, Laboratoire des Affections de la Myéline et des Canaux Ioniques Musculaires, Institut Fédératif des Neurosciences, CHU Pitié-Salpêtrière, Paris, France Mitotic activity persists in various regions of the adult mammal CNS. While evidences of neurogenesis appeared, many studies focused on the features of the adult stem cells from germinative areas such as the subventricular zone of the lateral ventricles, the dentate gyrus of the hippocampus, the cortex, the fourth ventricle and the central canal of the spinal cord. In the present paper, we review the potentialities of the adult germinative areas in terms of proliferation, migration and differentiation in non pathological situation and in response to different type of CNS injury. Adult endogenous stem cells are activated in response to various injuries but their capacities to migrate and to undergo either neurogenesis or gliogenesis differ according to the lesion-type and the germinative zone from which they arise. Different works demonstrated that epigenic factors such as growth factors can enhance the repair potential of the adult stem cells. Reactivation and mobilization of endogenous stem cells as well as demonstration of their long-term survival and functionality appear to be interesting strategies to investigate in order to promote endogenous repair of the adult CNS. © 2004 Wiley-Liss, Inc. Key words: neurogenesis, germinative zone, oligodendrogenesis, proliferation, migration The first evidence for neurogenesis in the adult central nervous system (CNS) was published 40 years ago (Altman and Das, 1965; Lewis, 1968; Altman, 1969; Privat and Leblond, 1972), but the notion that new neurons are generated really has found acceptance during the last decade. The use of proliferation markers such as tritiated thymidine, 5-bromo-2⬘-desoxyuridine (BrdU), and retroviral labeling highlighted neuronal renewal in at least two areas of the adult mammalian brain, the granule cell layer (GCL) of the dentate gyrus (DG) in the hippocampus and the olfactory bulb (OB). These new neurons are generated, respectively, from the subgranular zone (SGZ) of the DG and the subventricular zone (SVZ) of the lateral ventricles. In vitro studies have underscored the stem cell properties of cells residing in these germinative areas. Adult neural stem cells have been shown to display undifferentiated, self-renewable, and multipotent features. © 2004 Wiley-Liss, Inc. The neural stem cell is considered as a primary progenitor that is the precursor of a multipotent secondary progenitor. The secondary progenitor then gives rise to a precursor committed to a specific lineage of the CNS. Although the primary progenitor (stem cell) appears to have astroglial characteristics in the adult CNS, it retains the capacity to undergo neurogenesis (Alvarez-Buylla et al., 2002; Tramontin et al., 2003). Since the neurogenerative capacity of the adult CNS was established, many strategies designed to repair neurodegenerative diseases have been developed. Most studies explore the potential for repair by embryonic or perinatal stem cells using transplantation paradigms. However, the use of perinatal material implies ethical considerations, the availability of the cells, and their amplification and manipulation in vitro prior to intra-CNS transplantation. However, cell therapy may not be the most optimal strategy to enhance repair in multifocal diseases, such as multiple sclerosis (MS). The ability to isolate neural stem cells from the adult human brain raises the possibility of autologous transplantation. Therefore, experimental strategies designed to enhance reactivation and mobilization of endogenous stem cells have appeared and may lead to novel therapeutic approaches to neurodegenerative or demyelinating diseases. In this paper, we review the germinative areas of the adult mammalian CNS and summarize their potentialities in terms of cell reactivation, migration, and self-repair of the injured CNS. THE SVZ The SVZ is a remnant of the enlarged perinatal periventricular germinative area. During development, this germinative area narrows to the most rostral part of the lateral ventricle and forms the SVZ, which persists through *Correspondence to: Anne Baron-Van Evercooren, U546, Laboratoire des Affections de la Myéline et des Canaux Ioniques Musculaires IFRNS, Faculté de Médecine Pitié-Salpêtrière, 105 bd. de l’Hôpital, 75634 Paris Cedex 13, France. E-mail: [email protected] Received 22 October 2003; Revised 3 November 2003; Accepted 5 November 2003 Published online 8 March 2004 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.20040 224 Picard-Riera et al. adulthood (Tramontin et al., 2003). During development the SVZ generates the three major cell types of the CNS, but only neurogenesis persists in adulthood. However, in vitro, the adult SVZ stem/progenitor cells can be expanded in serum-free medium containing epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF-2) and form neurospheres, which generate neurons and glia (Reynolds and Weiss, 1992; Lois and AlvarezBuylla, 1993). However, in vivo, BrdU and retroviral tracing demonstrates that only neurogenesis occurs in the OB, from SVZ cells migrating through the rostral migratory stream (RMS; Luskin, 1993; Lois and Alvarez-Buylla, 1994; Lois et al., 1996). The nature of the stem cells in the SVZ is a subject of controversy. According to the original theory, the SVZ stem cells are ependymal cells lining the lateral ventricle (Johansson et al., 1999), whereas other authors claim that the stem cells originate from the subependymal layer of the lateral ventricle (Morshead et al., 1994; Chiasson et al., 1999). Eventually, this latter theory was confirmed by the work of Alvarez-Buylla and colleagues, identifying the SVZ stem cell as a subependymal cell with a low proliferation rate (Doetsch et al., 1999). Electron microscopy studies show that SVZ stem cells have the ultrastructural characteristics of astrocytes, which extend a single cilia into the ventricle lumen through the ependymal barrier (Tramontin et al., 2003). A nomenclature for the SVZ organization was established by the Tramontin et al. group. The slowly proliferating stem cells expressing glial fibrillary acidic protein (GFAP; type B cells) differentiate to become rapidly dividing immature progenitors (type C cells) and generate neuroblasts (type A cells), which migrate in chain through the RMS to the OB. It has recently been demonstrated that the RMS and the OB also contain stem cells and thus can be considered by themselves as germinative areas (Gritti et al., 2002). In this study, although all regions gave rise to neurons, astrocytes, and oligodendrocytes, in vitro, the rostral part of the RMS generated more oligodendrocytes. Cells arising from the SVZ and migrating through the RMS to the OB were also described for the adult primate forebrain (Pencea et al., 2001a; Kornack and Rakic, 2001). Although a detailed study of the localization of neural stem cells in the adult human brain is still lacking, neurospheres can be generated from the adult human subependymal zone of the lateral ventricle. Similarly to the case for rodents, these adult human neurospheres give rise to functional neurons and glia (Kukekov et al., 1999; Westerlund et al., 2003). However, they seem to have a limited life span in culture and generate very few oligodendrocytes (Kukekov et al., 1999; Roy et al., 2000). Neural stem cells can also be isolated from the adult human OB (Pagano et al., 2000). They display the same characteristics as human embryonic stem cells (Vescovi et al., 1999). They self-renew in vitro with EGF and FGF-2 and retain their multipotentiality. However, whereas embryonic stem cells keep these properties as long as 2 years, adult OB stem cells have been studied only until 40 days in vitro. Several models have been utilized to determine the real involvement of SVZ cells in CNS repair of acute or chronic injury. Most of these models have involved rodents and have demonstrated that SVZ cells are reactivated in response to different insults. Indeed, the proliferation rate of SVZ cells is increased after seizure (Parent et al., 2002), ischemia (Zhang et al., 2001; Arvidsson et al., 2002; Takasawa et al., 2002), transection (Weinstein et al., 1996), and also demyelination (Calza et al., 1998; NaitOumesmar et al., 1999; Picard-Riera et al., 2002). Recent studies have shown reactivation of the SVZ in the brains of patients affected with Huntington’s disease (Curtis et al., 2003) and in nonhuman primates exposed to ischemia (Tonchev et al., 2003). However, reactivation of the SVZ in demyelinating diseases, such as MS, has not been reported so far. The mobilization and recruitment of SVZ cells by lesions and their subsequent differentiation have been assessed in most of these models. After pilocarpine-induced status epilepticus in rats, Lowenstein and colleagues demonstrate that SVZ cells migrate more numerously in the RMS, although some are ectopically recruited in the neighboring injured regions to differentiate into neuronal precursors (Parent et al., 2002). However, few of these SVZ-derived neurons survive after a period of 5 weeks, and that they differentiate appropriately and are incorporated into the normal circuitry has not been demonstrated. The induction of stroke by transient middle artery occlusion is a model of focal ischemia that leads to the selective death of striatal neurons. When stroke is induced in adult rats, SVZ cells are selectively recruited in the injured striatum, whereas this phenomenon rarely occurs in the contralateral noninjured striatum (Arvidsson et al., 2002). Recruited cells coexpress doublecortin (Dcx), a marker of migrating neuroblasts, and Meis2, a specific marker of medium-sized spiny neurons of the striatum. Four weeks after stroke, the number of mature neurons increases, indicating that the neuroblasts underwent differentiation. However, functional evidence was not provided by this study. The authors indicated that 80% of newly generated neurons die between 2 and 6 weeks postischemia and that only a small proportion (about 0.2%) of striatal neurons are replaced. By using global ischemia, which selectively induces CA1 pyramidal neuron death, coupled to growth factor (EGF and FGF-2) infusion, Nakafuku and colleagues selectively traced caudal SVZ cells and demonstrated that they are mobilized to the CA1 region of the hippocampus, where they contribute to the replacement of pyramidal neurons (Nakatomi et al., 2002). Retrograde labeling, electron microscopy, and electrophysiology show that these newly generated neurons receive synaptic inputs and establish connections between the CA1 domain and the subiculum. Hippocampal neurons are involved in learning and memory functions, so testing in a Morris water maze has confirmed the recovery of brain functions. Although the neurogenic potential of adult SVZ cells in brain repair has been investigated, few authors have asked whether these cells could also generate oligoden- Neural Stem Cells and CNS Repair drocytes. During early postnatal development, SVZ cells generate oligodendrocytes whose fate is to integrate into white matter (Levison and Goldman, 1993). This activity persists in the brain of juvenile animals but ceases during adulthood. We assessed the reactivation of adult SVZ cells in murine models of focal (Nait-Oumesmar et al., 1999) and multifocal inflammatory demyelination, experimental autoimmune encephalomyelitis (EAE; Picard-Riera et al., 2002). In both models, the demyelination induces the proliferation of cells in the SVZ, their robust migration in the RMS, and their mobilization to the lesion sites. In both cases, cells differentiate into astrocytes and oligodendrocytes, whereas inflammation leads only to astroglial differentiation. In the multifocal model of EAE, cells are not exclusively recruited in the corpus callosum but are also found in the striatum. However, their mobilization seems to be restricted to the regions in the vicinity of the SVZ and RMS. Some of the SVZ cells undergo oligodendrogenesis after demyelination in the corpus callosum and also in the OB. Three weeks after EAE induction, cell death is not observed, suggesting that these newly generated oligodendrocytes are not the target of inflammatorydemyelination within this time frame. However, the fate and functionality of these oligodendrocytes in terms of myelin repair have yet to be demonstrated. To date, the mechanisms involved in the proliferation and mobilization of SVZ cells in response to inflammatory demyelination are unknown. However, Aloe and colleagues reported that this phenomenon seemed to be correlated with a selective uptake of 125I-nerve growth factor, suggesting that nerve growth factor could participate in these phenomena (Calza et al., 1998). Studies of the SVZ’s response to injury in human and nonhuman primate brains are rarely undertaken. Recently, evidence of induced neurogenesis was suggested in a macaque model of ischemia (Tonchev et al., 2003). Although migration was not assessed, the authors demonstrated increased proliferation in the SVZ compared with control animals. This study demonstrated the activation of a population of mitotic cells with a neuronal, astroglial or oligodendroglial phenotype. Moreover, a recent study reported the induction of proliferation in the SVZ of patients affected with Huntington’s disease (Curtis et al., 2003). The rate of proliferation, assessed by PCNA labeling, increased with the severity of the disease. The authors gave evidence of disease-induced neurogenesis and described the emergence of proliferative neuroblasts in the injured caudate nucleus. Reactivation of the SVZ in demyelinating diseases, such as MS, has not been reported so far. Our preliminary studies using MS tissues highlight the detection of PSA-NCAM-expressing progenitors in some types of lesions (Picard-Riera, unpublished data). Whether these cells arise from the SVZ is currently under investigation. Taken together, these different models reveal the ability of SVZ cells to undergo increased proliferation, ectopic migration, and multipotential differentiation. This differentiation is lesion specific, insofar as trauma induces 225 astroglial differentiation, a loss of neurons favors neuronal differentiation, and oligodendrogenesis occurs essentially in response to demyelination. Thus, it seems that local cues originating either from the lesion or from the environment in which cells migrate are important to direct their differentiation into the appropriate cell fate. Although SVZ cells reactivate in response to injury, they do not display a massive replacement, and newly generated neurons do not represent a stable population. As previously suggested by Lindvall and colleagues (Arvidsson et al., 2002), the functional integration and long-term survival of these newly generated cells have to be further investigated to determine the extent to which SVZ cells can participate in self-repair. THE HIPPOCAMPUS The DG of the hippocampus has also been extensively studied. Stem cells originating from the SGZ of the DG migrate into the GCL, where they differentiate into granule neurons that extend axons to the CA3 region (Altman and Das, 1965; Bayer, 1982; Kaplan and Bell, 1984; Kuhn et al., 1996). Gage and colleagues studied rodent SGZ cells in vitro and found that their stem cells retain the potential for self-renewal and the ability to differentiate into neurons, astrocytes, and oligodendrocytes (Palmer et al., 1997). In mice, the proliferative cells of the SGZ give rise to neurons, astrocytes, and oligodendrocyte progenitors (van Praag et al., 2002). The newly generated neurons integrate correctly into the hippocampal circuitry. Neurogenesis also occurs in the SGZ of tree shrews (Gould et al., 1997), nonhuman primates such as macaques (Gould et al., 1999b, 2001; Kornack and Rakic, 1999), marmosets (Gould et al., 1998), and humans (Eriksson et al., 1998). Furthermore, an in vivo study performed in Old World monkeys reported the generation of astrocytes and oligodendrocytes in the DG (Kornack and Rakic, 1999). SGZ cells of the adult human brain were also studied in vitro, confirming their stem cell features (Kukekov et al., 1999; Roy et al., 2000). Questions arise about the phenotype of the primordial stem cells of the SGZ. Alvarez-Buylla and colleagues demonstrated that GFAP-expressing cells of the SGZ can generate neurons of the GCL (Seri et al., 2001). The same work also demonstrated that a cell organization similar to that described for the SVZ exists in the hippocampus. In the SGZ, a weakly proliferative stem cell expressing GFAP (type B cell) gives rise to a small, dark, transient cell (type D cell), specific to the SGZ, that finally generates a GCL neuron. Several works have underscored the transient existence of these new neurons in both rodents (Cameron et al., 1993; Gould et al., 1999a) and Old World monkeys (Gould et al., 2001). In contrast, a recent study performed in mice highlighted the long-term persistence of newly generated neurons in the hippocampus, which were detected as late as 11 months after BrdU labeling (Kempermann et al., 2003). Animal models of neurological diseases are also used to investigate the potential for repair of the SGZ. Seizure induces proliferation in the rodent SGZ, increasing the 226 Picard-Riera et al. proliferation rate of progenitor cells (Parent et al., 1997, 2002; Bengzon et al., 1997). Ischemia accelerates proliferation in rodents (Liu et al., 1998; Jin et al., 2001; Nakatomi et al., 2002; Takasawa et al., 2002; Dempsey et al., 2003) and also in nonhuman primates (Tonchev et al., 2003). Although SGZ cells normally undergo shortdistance migration to integrate into the GCL, long- distance migration does not seem to occur in pathological models. Many studies have highlighted the presence of lesion-induced neurogenesis in the hippocampus. Sharp and colleagues induced transient global ischemia in gerbils and traced proliferative cells of the DG by using BrdU injections (Liu et al., 1998). The observation of BrdUlabeled cells at different time points allowed the authors to establish their pattern of migration and differentiation. Fifteen days after ischemia, most of the BrdU-positive cells were located in the SGZ but did not express NeuN. From 26 to 40 days after ischemia, traced cells progressively migrated to the GCL, where finally 61% of them expressed NeuN. Interestingly, the control animals also displayed an increased number of double-labeled NeuN/ BrdU cells between days 26 and 40, confirming that neurogenesis occurs under normal conditions. Moreover, SGZ cells also undergo astrogliogenesis. Some SGZ progenitors migrate to the hilus to generate astrocytes, whereas a proportion of the cells that migrate to the DG and the dentate hilus remains unidentified. These unlabeled cells could be either undifferentiated progenitors or oligodendrocytes, the latter cell type having rarely been investigated. Neurogenesis in the hippocampus has also been demonstrated in various models of focal ischemia in the rat (Jin et al., 2001; Arvidsson et al., 2001; Takasawa et al., 2002; Dempsey et al., 2003) and global ischemia in macaque monkeys (Tonchev et al., 2003). All these studies demonstrate that new SGZ-derived neurons are able to replace lost neurons and to restore function of the hippocampus. In pathologies, SGZ cells are reactivated, migrate over a short distance, and undergo neurogenesis. The long-term persistence of newly generated neurons has been demonstrated in the noninjured hippocampus, but this property remains to be confirmed Š Fig. 1. The adult rodent brain contains areas with mitotic activity. A: The subventricular zone (SVZ) contains proliferative cells (red dots) lining the rostral part of the lateral ventricle. In nonpathological situations, these cells migrate along the rostral migratory stream (RMS) to generate new neurons in the olfactory bulb. In response to injury, these cells can migrate ectopically into the striatum or the corpus callosum or caudally toward the CA1 region of the hippocampus. Under these conditions, SVZ cells retain the capacity to differentiate into astrocytes, oligodendrocytes, and neurons. Some of them migrate into the cortex to maintain the existence of resident progenitors. Those progenitors seem to be glial ones, and whether they can undergo neurogenesis remains controversial. B: In the hippocampus, stem cells reside in the subgranular zone (SGZ) of the dentate gyrus (DG). These cells migrate to the granule cell layer (GCL) to differentiate into neurons, extending axons to the CA3 area of the hippocampus. They also generate some astrocytes and oligodendrocytes in the GCL. In response to lesions, SGZ cells migrate in large numbers to the GCL to add more neurons, some of them being functional. These cells also undergo gliogenesis in the hilus (h); they give rise to astrocytes and undetermined cells that could be oligodendrocytes. C: In the spinal cord, progenitors exist in the ependymal layer and the parenchyma. Cells generated in response to a lesion are essentially glia, although a few neurons have been reported. OB, olfactory bulb; V, ventricle; GM, gray matter; WM, white matter. Neural Stem Cells and CNS Repair in pathological conditions. Moreover, although stem cells from the hippocampus display some glial differentiation, their ability to repair traumatic or demyelinating lesions is still unclear. THE CORTEX Unlike the case for the SVZ and the SGZ, few studies have identified neural stem cells in the rodent cortex. However, neural stem cells have been isolated from the human cortex and amygdala (Arsenijevic et al., 2001). Recently, resident glial precursors were isolated from human subcortical white matter (Nunes et al., 2003). These precursors appear to be multipotential cells retaining the ability to undergo both neurogenesis and gliogenesis in vitro and following transplantation. Gross and colleagues report the genesis of new neurons in the neocortex of adult macaque monkeys (Gould et al., 1999c). These cells arise from the SVZ and migrate through the white matter to integrate into the neocortex, where they differentiate into mature neurons. This ventricular-cortical migration may be a remnant of the waves of tangential migration observed from the lateral and medial ganglionic eminences to the neocortex during development (Corbin et al., 2001). However, two studies performed in macaques were not in agreement with these data and, in contrast, demonstrated that BrdU-positive cells detected in the neocortex are in fact satellite glial cells closely apposed to resident neurons (Kornack and Rakic, 2001; Koketsu et al., 2003). These studies underscore the necessity to perform detailed confocal analysis and threedimensional reconstruction to establish unambiguously the origin of newly generated neurons and glia in the adult CNS. However, in pathological situations, in situ cortical neurogenesis can occur. The induction of synchronous apoptotic degeneration of specific neurons of the anterior cortex in adult mice leads to the replacement of lost neurons (Magavi et al., 2000). In this study, neurogenesis was confirmed using three-dimensional reconstruction. Moreover, some of the newly generated neurons were mature neurons forming long-distance corticothalamic connections. Though not investigated, these cells may also be activated in response to demyelination and participate in myelin repair. THE SPINAL CORD AND THE FOURTH VENTRICLE Because neurogenesis occurs in the adult SVZ, such a phenomenon is likely to occur through the entire ventricular neuroaxis. Reynolds and colleagues tested this hypothesis by evaluating the in vitro characteristics of different regions of the rodent spinal cord (Weiss et al., 1996). Cells from various dorsoventral regions of the spinal cord and the third and the fourth ventricle were expanded in medium enriched with EGF and FGF-2. All these regions display self-renewal and multipotential features of stem cells. The lumbosacral segment of the spinal cord is defined as the area providing the greatest number of multipotent cells with close similarities to cultures from 227 the lateral ventricles. However, the nature of the stem cell in the ependyma remains to be elucidated. Mitotic activity, though discrete, also exists around the fourth ventricle (Martens et al., 2002). Further investigations must be performed to determine the potential for reactivation in this area. In vitro, FGF-2 alone is sufficient to give rise to both neurons and glia in all spinal cord regions (Shihabuddin et al., 1997). Proliferating cells of the spinal cord reside not only in the ependymal layer of the central canal but also in the parenchyma (Horner et al., 2000). In nonpathologic conditions, these cells are glial progenitors; they generate essentially astrocytes and oligodendrocytes but not neurons. Ependymal and parenchymal progenitors are activated in response to spinal cord transection (Yamamoto et al., 2001). They proliferate and constitute approximatively 12% of the BrdU-labeled cells in the parenchyma, and, when isolated in vitro, they generate astrocytes and oligodendrocytes but few neurons. Questions persist about the precise nature and origin of these cells. Do they arise from the ependyma or the parenchyma? Do they have similar multipotential features? Gage and colleagues hypothesized two models to explain adult neurogenesis in the spinal cord (Horner et al., 2000). In the first, both ependymal and parenchymal proliferative cells are stem cells; in the second, the ependymal cell is a stem cell whose progeny migrates to the parenchyma to become a resident progenitor. Strategies should be envisioned to label each of these populations specifically and to determine their cell fate. Immature progenitors expressing PSA-NCAM in the absence of other markers and originating from the ependyma are also observed in response to focal demyelination (Oumesmar et al., 1995). However, their contribution to myelin repair remains to be established. FACTORS STIMULATING ENDOGENOUS STEM CELLS In vivo, the fate of SVZ cells is neurogenesis; however, growth factor infusion is able to direct cell differentiation toward astrocytes and oligodendrocytes in addition to neurons (Craig et al., 1996). SVZ cells retain the capacity to migrate both rostrally and caudally and to differentiate into the appropriate phenotype. However, it appears that this migration is quite limited and that differentiation does not always imply adequate functionality. The infusion of growth factors in nonpathological conditions can enhance proliferation and trigger the mobilization and differentiation of SVZ cells. The infusion of EGF increases cell proliferation in the SVZ and the olfactory tract and favors gliogenesis rather than neurogenesis (Craig et al., 1996; Kuhn et al., 1997). Whereas EGF enhances the migration and dispersion of cells in the parenchyma surrounding the olfactory tract, FGF-2 enhances cell proliferation in the SVZ and neurogenesis in the OB (Kuhn et al., 1997; Wagner et al., 1999). In aged animals, transforming growth factor-␣ (TGF-␣) and FGF-2 return the proliferation rate of SVZ cells to that of young adults (Tropepe et al., 1997; Decker et al., 2002). 228 Picard-Riera et al. Growth factor treatment enhances the contribution of stem cells to repair mechanisms. The infusion of FGF-2 and EGF induces a 50-fold increase in neurogenesis from the SVZ in response to ischemia (Nakatomi et al., 2002). We found that priming SVZ cells by a single injection of FGF-2 prior to intra-CNS grafting enhances their ability to form myelin in recipients (Lachapelle et al., 2002). TGF-␣ treatment induced the migration and differentiation of SVZ progenitors in a Parkinson’s disease model in the rat (Fallon et al., 2000). Cells migrated to the site of TGF-␣ infusion, in the striatum, where they differentiated into neurons. Although the functionality of the newly generated neurons was not physiologically assessed, the activation of the SVZ cells and their migration/ differentiation to the site of injury were correlated with the recovery of functional activity; the treated animals displayed improvement in behavioral tests. In chemically demyelinated mice, an intraperitoneal injection of FGF-2 or TGF-␣ increases the number of SVZ cells recruited to the lesion in young adults but not aged animals (Decker et al., 2002). Insofar as aged and young adult SVZ cells possess a similar potential for migration in vitro, these data highlight the crucial role of the lesioned environment in the recruitment of SVZ cells. Brain-derived neurotrophic factor (BDNF) improves the recruitment of SVZ cells to the OB and stimulates their differentiation into neurons (Zigova et al., 1998; Pencea et al., 2001b; Benraiss et al., 2001). In the hippocampus, growth factors act on proliferation and neurogenesis rather than on migration. Under normal conditions, IGF-1 is reported to increase hippocampal proliferation and neurogenesis (Aberg et al., 2000). The same growth factor, as well as glia-derived neurotrophic factor (GDNF), increases proliferation and survival time of progenitors in ischemic rats (Dempsey et al., 2003). Although FGF-2 seems to promote only neurogenesis under nonpathological situation (Kuhn et al., 1997; Wagner et al., 1999), the effect of FGF-2 was assessed in homozygous FGF-2-deficient mice subjected to either seizure or ischemia (Yoshimura et al., 2001). FGF-2–/– mice displayed reduced BrdU incorporation and a decreased number of NeuN/BrdU double-labeled cells compared with wild-type mice. Exogenous FGF-2 allowed this situation to be overcome. Interestingly, no proliferation differences appeared between FGF-2deficient and wild-type mice under nonpathological conditions, confirming the above-mentioned result showing no effects of FGF-2 on cell proliferation under normal conditions. However, intracisternal infusion of FGF-2 promotes proliferation and neurogenesis in the DG of rats after focal ischemia (Wada et al., 2003). Injury may either favor FGF-2 uptake by cells or reactivate a population of cells responsive to this growth factor. The reduced mitotic activity of the fourth ventricle can be emphasized by using an infusion of EGF, FGF-2, and heparin (Martens et al., 2002). These growth factors promote proliferation in the whole ventricular neuroaxis, whereas EGF induces the migration of cells from the fourth ventricle and the ependymal layer of the spinal cord. The origin of the proliferative cells found in the spinal cord may be controversial; some of them may be resident progenitors of the parenchyma. Similarly, in the fourth ventricle, as in the spinal cord, some cells have differentiated into astrocytes or oligodendrocytes but not into neurons. Thyroid hormone has been shown to be a factor enhancing oligodendrogenesis in EAE rats (Calza et al., 2002). Whereas EAE promotes the increased proliferation of progenitors in the spinal cord of rats, treatment with the thyroid hormone T4 leads to reduced mitotic activity and favors their differentiation into oligodendrocytes. These results suggest that different growth factors could be administered in different time windows first to enhance proliferation and migration and subsequently to stimulate differentiation. In addition to the growth factors described above, morphogens, such as bone morphogenic proteins (BMPs), Shh, and Wnt signalling, regulate the proliferation and differentiation of SVZ neural stem cells. For instance, several lines of evidences support a role of Shh in adult neural stem cell proliferation and maturation (Lai et al., 2003). Furthermore, it was recently reported that oral administration of a Shh agonist increased the number of proliferating cells in the adult SVZ and hippocampal DG. This effect is mediated by an up-regulation of Gli1 signalling (Machold et al., 2003). However, the nature of the cells that produce Shh in the SVZ and DG remains unclear. These data suggest that this morphogen may also play a critical role in the pathological status of the adult mammalian brain. It may be possible to take advantage of the continuous expression of Shh in adult germinative zones to develop new therapeutic drugs for neural disorders. BMPs and their antagonist Noggin also play a critical role in the proliferation and differentiation of adult SVZ stem/progenitor cells (Lim et al., 2000). SVZ cells express BMPs and their cognate receptors. BMPs potently inhibit neurogenesis both in vitro and in vivo and promote glial differentiation. In contrast, Noggin promotes neurogenesis in vitro and inhibits glial cell differentiation. Lim et al. proposed that ependymal Noggin secretion creates a neurogenic niche in the SVZ by blocking BMP signaling. Insofar as this mechanism is relatively well understood under normal conditions, it will be of interest to investigate whether the expression profiles of these molecules are changed following brain damage. In fact, it has recently been reported that the intravenous administration of BMP7 has neuroprotective effects and induces neuronal repair in cerebral stroke in adult rats (Chang et al., 2003). Other epigenetic factors influence neurogenesis in both hippocampal and olfactory structures. Mice exposed to an enriched olfactory environment display increased neurogenesis and survival time of the new neurons (Rochefort et al., 2002). The absence of changes in hippocampal proliferation indicates that this neurogenesis is specific for olfactory function. However, stress decreases proliferation in the SGZ in rats (Gould and Cameron, 1996), tree shrews (Gould et al., Neural Stem Cells and CNS Repair 1997), and marmosets (Gould et al., 1998), possibly through an increased concentration of glucocorticoı̈des, but this remains to be demonstrated (Cameron and Gould, 1994). Gross and colleagues indicate that new neurons added in the GCL have a transient existence (Gould et al., 2001). Several studies have demonstrated that an enriched environment, consisting of the addition of elements to create a three-dimensional environment, increases neurogenesis and, to a lesser extent, astrogliosis in the hippocampus of rodents (Kempermann et al., 1997a,b; van Praag et al., 2002). Interestingly, whereas odor enrichment is specific for OB neurogenesis, environmental enrichment induces neurogenesis only in the hippocampus (Brown et al., 2003). Neurogenesis seems to be intimately linked to the function of the structures in which it occurs. According to this hypothesis, it would be interesting to investigate the relative importance of olfactive vs. hippocampal neurogenesis in the human brain in which learning and memory may prevail over olfaction. The impact of an enriched environment on oligodendrogenesis in pathological and nonpathological conditions has not been investigated to date. These results suggest that “laboratory” studies performed in nonenriched environments may underestimate the extent of the neurogenesis and gliogenesis that would occur if animals were studied in their natural environment. CONCLUSIONS Both the SVZ and the SGZ retain the potential to increase cell proliferation and neurogenesis in response to various insults. Although SGZ cell migration seems to be limited to the DG and the hilus of the hippocampus, even in pathological situations, SVZ cells, whose fate is to migrate rostrally to the OB, can alter this migration to escape prematurely into neighboring areas, such as the striatum and corpus callosum. Taking advantage of their caudal migration, SVZ cells can also ectopically invade the CA1 layer of the hippocampus. Hippocampal and SVZ stem/progenitor cells generate neurons, some of which are functional, but also astrocytes and oligodendrocytes in response to injury. The real involvement of the other germinative zones under pathological conditions should be further investigated. Moreover, the long-term effects of neurogenesis and gliogenesis remain elusive. Do the new neurons accurately integrate into neuronal circuitry, and do oligodendrocytes undergo effective remyelination? Because white matter oligodendrocyte progenitors participate in myelin repair, it will be important to determine the advantages of the new oligodendrocyte progenitors derived from germinative zones over the resident white matter ones. Because neurogenesis and oligodendrogenesis from germinative areas remain a restricted phenomenon, efforts should focus on the cues promoting the long-term survival and functional differentiation of endogenous stem/progenitor cells to repair the injured CNS efficiently. 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