Radial glial origin of the adult neural stem cells in the subventricular zone

Adult neurogenesis persists within restricted areas of the mammalian brain, giving rise prevalently to neuronal precursors that integrate inside the hippocampus and olfactory bulb. The source of this continuous cell production consists of neural stem cells which have been identified as elements of the astroglial lineage. This counterintuitive finding overlaps with the recent discovery that embryonic radial glia can themselves act as stem cells, capable of producing both neurons and glia during development. Although radial glia was thought to disappear early postnatally at the end of neurogenesis by transformation into parenchymal astrocytes, it has recently been demonstrated that some radial glial cells somehow persist within the adult forebrain subventricular zone, hidden among astrocytes of the glial tubes. This transformation occurs in parallel with overall morphological and molecular changes within the neurogenic site, whose specific steps, mechanisms, and outcomes are not yet fully understood. The modified radial glia appear to be neural progenitor cells belonging to the astroglial lineage (type B cells) assuring both stem cell self-renewal and production of a differentiated progeny in the adult subventricular zone, and also playing regulatory roles in stem cell niche maintenance.     

Cell migration in the normal and pathological postnatal mammalian brain

In the developing brain, cell migration is a crucial process for structural organization, and is therefore highly regulated to allow the correct formation of complex networks, wiring neurons, and glia. In the early postnatal brain, late developmental processes such as the production and migration of astrocyte and oligodendrocyte progenitors still occur. Although the brain is completely formed and structured few weeks after birth, it maintains a degree of plasticity throughout life, including axonal remodeling, synaptogenesis, but also neural cell birth, migration and integration. The subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus are the two main neurogenic niches in the adult brain. Neural stem cells reside in these structures and produce progenitors that migrate toward their ultimate location: the olfactory bulb and granular cell layer of the DG respectively. The aim of this review is to synthesize the increasing information concerning the organization, regulation and function of cell migration in a mature brain. In a normal brain, proteins involved in cell–cell or cell–matrix interactions together with secreted proteins acting as chemoattractant or chemorepellant play key roles in the regulation of neural progenitor cell migration. In addition, recent data suggest that gliomas arise from the transformation of neural stem cells or progenitor cells and that glioma cell infiltration recapitulates key aspects of glial progenitor migration. Thus, we will consider glioma migration in the context of progenitor migration. Finally, many observations show that brain lesions and neurological diseases trigger neural stem/progenitor cell activation and migration toward altered structures. The factors involved in such cell migration/recruitment are just beginning to be understood. Inflammation which has long been considered as thoroughly disastrous for brain repair is now known to produce some positive effects on stem/progenitor cell recruitment via the regulation of growth factor signaling and the secretion of a number of chemoattractant cytokines. This knowledge is crucial for the development of new therapeutic strategies. One of these strategies could consist in increasing the mobilization of endogenous progenitor cells that could replace lost cells and improve functional recovery.     

PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo

We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a-Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-B into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-B caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.     

Radial glia-like cells at the base of the lateral ventricles in adult mice

During development radial glia (RG) are neurogenic, provide a substrate for migration, and transform into astrocytes. Cells in the RG lineage are functionally and biochemically heterogeneous in subregions of the brain. In the subventricular zone (SVZ) of the adult, astrocyte-like cells exhibit stem cell properties. During examination of the response of SVZ astrocytes to brain injury in adult mice, we serendipitously found a population of cells in the walls of the ventral lateral ventricle (LV) that were morphologically similar to RG. The cells expressed vimentin, glial fibrillary acidic protein (GFAP), intermediate filament proteins expressed by neural progenitor cells, RG and astrocytes. These RG-like cells had long processes extending ventrally into the nucleus accumbens, ventromedial striatum, ventrolateral septum, and the bed nucleus of the stria terminalis. The RG-like cell processes were associated with a high density of doublecortin-positive cells. Lesioning the cerebral cortex did not change the expression of vimentin and GFAP in RG-like cells, nor did it alter their morphology. To study the ontogeny of these cells, we examined the expression of molecules associated with RG during development: vimentin, astrocyte-specific glutamate transporter (GLAST), and brain lipid-binding protein (BLBP). As expected, vimentin was expressed in RG in the ventral LV embryonically (E16, E19) and during the first postnatal week (P0, P7). At P14, P21, P28 as well as in the adult (8-12 weeks), the ventral portion of the LV retained vimentin immunopositive RG-like cells, whereas RG largely disappeared in the dorsal two-thirds of the LV. GLAST and BLBP were expressed in RG of the ventral LV embryonically and through P7. In contrast to vimentin, at later stages BLBP and GLAST were found in RG-like cell somata but not in their processes. Our results show that cells expressing vimentin and GFAP (in the radial glia-astrocyte lineage) are heterogeneous dorsoventrally in the walls of the LV. The results suggest that not all RG in the ventral LV complete the transformation into astrocytes and that the ventral SVZ may be functionally dissimilar from the rest of the SVZ.     

Selective upregulation of 3-phosphoglycerate dehydrogenase (Phgdh) expression in adult subventricular zone neurogenic niche

In the adult rodent brain, constitutive neurogenesis occurs in two restricted regions, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus, where multipotent neural stem/progenitor cells generate new neurons. Using Western blotting and immunohistochemistry for established markers, we demonstrated that the expression of 3-phosphoglycerate dehydrogenase (Phgdh), an enzyme involved in de novo synthesis of l-serine, was upregulated in the SVZ. The expression was selective to cells having morphological features and expressing markers of astrocyte-like primary neural stem cells (type B cells) and their progeny, actively proliferating progenitors (type C cells). By contrast, Phgdh protein expression was virtually absent in committed neuronal precursors (type A cells) derived from type C cells. High levels of Phgdh were also expressed by glial tube cells located in the rostral migratory stream (RMS). Interestingly, ensheathment of type A cells by these Phgdh-expressing cells was persistent in the SVZ and RMS, suggesting that l-serine mediates trophic support for type A cells via these glial cells. In vitro neurosphere assays confirmed that growth-factor-responsive, transient amplifying neural progenitors in the SVZ, but not differentiated neurons, expressed Phgdh. In the aged brain, a decline in Phgdh expression was evident in type B and C cells of the SVZ. These observations support the notion that availability of l-serine within neural stem/progenitor cells may be a critical factor for neurogenesis in developing and adult brain.     

Induction of neurogenesis in nonconventional neurogenic regions of the adult central nervous system by niche astrocyte-produced signals

The central nervous system (CNS) of adult mammals regenerates poorly; in vivo, neurogenesis occurs only in two restricted areas, the hippocampal subgranular zone (SGZ) and the subventricular zone (SVZ). Neurogenic potential depends on both the intrinsic properties of neural progenitors and the environment, or niche, in which progenitor cells reside. Isolation of multipotent progenitor cells from broad CNS regions suggests that the neurogenic potential of the adult CNS is dictated by local environmental cues. Here, we report that astrocytes in the neurogenic brain regions, the SGZ and SVZ, of adult mice release molecular signals, such as sonic hedgehog (Shh), that stimulate adult neural progenitors to reenter the cell cycle and generate new neurons in vitro and in vivo. Transplantation of SGZ astrocytes or application of Shh caused de novo neurogenesis from the non-neurogenic neocortex of adult mice. These findings identify a molecular target that can activate the dormant neurogenic potential from nonconventional neurogenic regions of the adult CNS and suggest a novel mechanism of neural replacement therapy for treating neurodegenerative disease and injury without transplanting exogenous cells.     

The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone

The tailless (Tlx) gene encodes an orphan nuclear receptor that is expressed by neural stem/progenitor cells in the adult brain of the subventricular zone (SVZ) and the dentate gyrus (DG). The function of Tlx in neural stem cells of the adult SVZ remains largely unknown. We show here that in the SVZ of the adult brain Tlx is exclusively expressed in astrocyte-like B cells. An inducible mutation of the Tlx gene in the adult brain leads to complete loss of SVZ neurogenesis. Furthermore, analysis indicates that Tlx is required for the transition from radial glial cells to astrocyte-like neural stem cells. These findings demonstrate the crucial role of Tlx in the generation and maintenance of NSCs in the adult SVZ in vivo.     

Cell division and apoptosis in the adult neural stem cell niche are differentially affected in transthyretin null mice

Thyroid hormones (THs) are fundamental in regulation of growth and development, particularly of the brain. THs are required for full proliferative activity of neural stem cells in the subventricular zone (SVZ) of adult mouse brains, and also affect the normal fate of progenitor cells: apoptosis. Transthyretin (TTR) is a TH distributor protein in the blood and cerebrospinal fluid. TTR secretion by the choroid plexus is involved in transport of THs from blood into cerebrospinal fluid. We investigated the regulation of neural stem cell cycle in the SVZ of adult TTR null mice. Markers for neural stem cell mitosis that are reduced during hypothyroidism, did not differ between genotypes. However, in TTR null mice the level of apoptosis, the fate of most progenitor cells, was as low as that in brains of hypothyroid wildtype mice. Thus, lack of TTR results in reduced availability of TH to progenitor cells in the SVZ. We show that proliferation and apoptosis in the SVZ neural stem cell niche are differentially affected by the lack of TTR synthesis.     

Roles of the mammalian subventricular zone in cell replacement after brain injury

The subventricular zones (SVZs) are essential sources of new cells in the developing brain and remnants of these germinal zones persist into adulthood. As these cells have the capacity to replenish neurons and glia that are turning over, many investigators have assessed the SVZ's role in replacing neural cells eliminated by brain injuries. A review of the literature reveals that the progenitors within the SVZs are vulnerable to chemical, radiation and ischemia-induced damage, whereas the neural stem cells are resilient. With moderate insults, the SVZ can recover, but it cannot recover after more severe injury. Thus, the vulnerability of these cells has important ramifications when considering therapeutic interventions for the treatment of brain tumors and for the prospect of recovery after ischemia. The cells of the perinatal and adult SVZ not only have the capacity to replenish their own numbers, but they also have the capacity to replace neurons and glia after ischemic and traumatic brain injuries. Moreover, the mechanisms underlying these regenerative responses are beginning to be revealed. By reviewing, comparing and contrasting the responses of the SVZs to different injuries, our goal is to provide a foundation from which current and future studies on the potential of the SVZs for cell replacement can be evaluated.     

Brain NGF and EGF administration improves passive avoidance response and stimulates brain precursor cells in aged male mice

Nerve growth factor (NGF) has been shown to improve damage in spatial cognition following aging, whereas epidermal growth factor (EGF) is important in brain cell proliferation. It is also known that the adult mammalian central nervous system contains persistent progenitor cells with characteristics of stem cells. These studies suggest that under appropriate external stimuli progenitor cells may generate neuronal and glial cells promoting recovery of the injured nervous system. However, little is known about the presence and responsiveness of progenitor cells in the aged brain. In the present investigation, we studied the effect of brain intracerebroventricular injections of EGF and/or NGF on progenitor cells of the subventricular area (SVZ) in aged male mice to test learning performances in the passive avoidance apparatus. We found that neither NGF nor EGF improved learning responses. However, combined NGF and EGF administration in the brain improved learning responses of aged mice in the passive avoidance when compared with aged matched nontreated controls. These findings resulted to be associated with increased immunopositivity to progenitor cells in the SVZ. The possible functional implications of these data are discussed.     

Reinduction of ErbB2 in astrocytes promotes radial glial progenitor identity in adult cerebral cortex

Radial glial cells play a critical role in the construction of mammalian brain by functioning as a source of new neurons and by providing a scaffold for radial migration of new neurons to their target locations. Radial glia transform into astrocytes at the end of embryonic development. Strategies to promote functional recovery in the injured adult brain depend on the generation of new neurons and the appropriate guidance of these neurons to where they are needed, two critical functions of radial glia. Thus, the competence to regain radial glial identity in the adult brain is of significance for the ability to promote functional repair via neurogenesis and targeted neuronal migration in the mature brain. Here we show that the in vivo induction of the tyrosine kinase receptor, ErbB2, in mature astrocytes enables a subset of them to regain radial glial identity in the mature cerebral cortex. These new radial glial progenitors are capable of giving rise to new neurons and can support neuronal migration. These studies indicate that ErbB2 signaling critically modulates the functional state of radial glia, and induction of ErbB2 in distinct adult astrocytes can promote radial glial identity in the mature cerebral cortex.     

Characterization of novel monoclonal antibodies able to identify neurogenic niches and arrest neurosphere proliferation and differentiation

Two monoclonal antibodies (Nilo1 and Nilo2) were generated after immunization of hamsters with E13.5 olfactory bulb-derived mouse neurospheres. They are highly specific for neural stem and early progenitor cell surface antigens. Nilo positive cells present in the adult mouse subventricular zone (SVZ) were able to initiate primary neural stem cell cultures. Moreover, these antibodies added to neurosphere cultures induced proliferation arrest and interfered with their differentiation. In the lateral ventricles of adult mice, Nilo1 stained a cell subpopulation lining the ventricle and cells located in the SVZ, whereas Nilo2 stained a small population associated with the anterior horn of the SVZ at the beginning of the rostral migratory stream. Co-staining of Nilo1 or Nilo2 and neural markers demonstrated that Nilo1 identifies an early neural precursor subpopulation, whereas Nilo2 detects more differentiated neural progenitors. Thus, these antibodies identify distinct neurogenic populations within the SVZ of the lateral ventricle.     

Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells

Recent studies have found that cellular self-renewal capacity in brain cancer is heterogeneous, with only stem-like cells having this property. A link between adult stem cells and cancer stem cells remains, however, to be shown. Here, we describe the emergence of cancer stem-like cells from in vitro cultured brain stem cells. Adult rat subventricular zone (SVZ) stem cells transformed into tumorigenic cell lines after expansion in vitro . These cell lines maintained characteristic features of stem-like cells expressing Nestin, Musashi-1 and CD133, but continued to proliferate upon differentiation induction. Karyotyping detected multiple acquired chromosomal aberrations, and syngeneic transplantation into the brain of adult rats resulted in malignant tumor formation. Tumors revealed streak necrosis and displayed a neural as well as an undifferentiated phenotype. Deficient downregulation of platelet-derived growth factor (PDGF) receptor alpha was identified as candidate mechanism for tumor cell proliferation, and its knockdown by siRNA resulted in a reduction of cell growth. Our data point to adult brain precursor cells to be transformed in malignancies. Furthermore, in vitro expansion of adult neural stem cells, which will be mandatory for therapeutic strategies in neurological disorders, also harbors the risk for amplifying precursor cells with acquired genetic abnormalities and induction of malignant tumors after transplantation.     

成年大鼠去皮层血管引起前脑室下区祖细胞增殖迁移并形成迁移路至损伤部位(二)来自背外侧脑室下区的祖细胞形成迁移路经胼胝体至损伤部位

近年来很多实验证明各种脑损伤和中枢神经疾病都能促进神经干细胞或祖细胞向非嗅球区域迁移,本研究将成年大鼠一侧大脑皮层血管去除,用免疫组化方法标记前脑室下区正在分裂的细胞、神经元祖细胞和胶质细胞祖细胞。结果证明:损伤侧及对侧的背外侧脑室下区各类祖细胞明显增多并向胼胝体迁移,在胼胝体内它们分别形成迁移路至损伤部位;迁移路内的各种祖细胞具有典型的不成熟的迁移细胞特点,胞体细长,一般首尾各有一突起,其引导突皆朝向损伤区。本研究结果提示去皮层血管增殖的前脑室下区神经元祖细胞和胶质细胞祖细胞通过放射状迁移路至损伤部位可能参与修复机制。     

Nitric oxide decreases subventricular zone stem cell proliferation by inhibition of epidermal growth factor receptor and phosphoinositide-3-kinase/Akt pathway

Nitric oxide (NO) inhibits proliferation of subventricular zone (SVZ) neural precursor cells in adult mice in vivo under physiological conditions. The mechanisms underlying this NO effect have now been investigated using SVZ-derived neural stem cells, which generate neurospheres in vitro when stimulated by epidermal growth factor (EGF). In these cultures, NO donors decreased the number of newly formed neurospheres as well as their size, which indicates that NO was acting on the neurosphere-forming neural stem cells and the daughter neural progenitors. The effect of NO was cytostatic, not proapoptotic, and did not involve cGMP synthesis. Neurosphere cells expressed the neuronal and endothelial isoforms of NO synthase (NOS) and produced NO in culture. Inhibition of NOS activity by N(omega)-nitro-L-arginine methylester (L-NAME) promoted neurosphere formation and growth, thus revealing an autocrine/paracrine action of NO on the neural precursor cells. Both exogenous and endogenous NO impaired the EGF-induced activation of the EGF receptor (EGFR) tyrosine kinase and prevented the EGF-induced Akt phosphorylation in neurosphere cells. Inhibition of the phosphoinositide-3-kinase (PI3-K)/Akt pathway by LY294002 significantly reduced the number of newly formed neurospheres, which indicates that this is an essential pathway for neural stem cell self-renewal. Chronic administration of l-NAME to adult mice enhanced phospho-Akt staining in the SVZ and reduced nuclear p27(Kip1) in the SVZ and olfactory bulb. The inhibition of EGFR and PI3-K pathway by NO explains, at least in part, its antimitotic effect on neurosphere cells and may be a mechanism involved in the physiological role of NO as a negative regulator of SVZ neurogenesis in adult mice.     

成年大鼠去皮层血管引起前脑室下区祖细胞增殖迁移并形成迁移路至损伤部位(一)祖细胞增殖迁移的部位在背外侧脑室下区

成年哺乳动物脑室下区(SVZ)富有神经干细胞、神经细胞祖细胞和胶质细胞祖细胞,它们能生成新的神经细胞、星状胶质细胞和少突胶质细胞。SVZ中的神经细胞祖细胞能形成切线形式的嘴侧迁移流(RMS)到嗅球,在嗅球分化成成熟的中间神经元。近年来证明成年动物实验性脑损伤和变性疾病都能引起SVZ细胞增生并能向非嗅球区迁移。本研究将成年大鼠一侧大脑皮层血管去除,15d和30d后取前脑作冠状及矢状连续切片,用BrdU和PCNA抗体显示前脑室下区正在分裂的细胞;用Tuj1抗体显示神经元祖细胞;用GFAP和vimentin抗体显示胶质细胞祖细胞。结果证明去除一侧皮层血管引起术侧及其对侧的背外侧脑室下区(dl-SVZ)的上述免疫反应阳性细胞明显增多,并向胼胝体迁移,在胼胝体内形成放射形式迁移路至损伤部位。本研究表明背外侧脑室下区的范围应包括背外侧角、外侧伸展和侧脑室上壁的SVZ,它们是切线形式和放射形式两种不同方向的迁移路祖细胞的共同源地。     

Comparison of neuron-like cells derived from bone marrow stem cells to those differentiated from adult brain neural stem cells

Bone marrow-derived stem/progenitor cells have been shown by independent investigators to give rise to neural-like cells (neurons and glia) both in vitro and in vivo. The objective of the present study was to determine whether nestin-enriched cells derived from bone marrow can differentiate into cells with the same morphological and functional characteristics as neurons derived from adult brain neurogenic zones. Cell culture methods were used for generation of adult bone marrow and brain stem/progenitor cells and for studying their differentiation into neural-like cells. The proportion of cells expressing neuronal markers was greater in cultures derived from adult hippocampal neural stem cells than in the bone marrow-derived cells, but the electrophysiological and functional characteristics of the cells were similar. Action potentials with electrical characteristics corresponding to those exhibited by adult neural stem cell-derived neurons were recorded from approximately 2.5% of patched neuron-like cells differentiated from bone marrow cells. The active uptake of tritium-labeled neurotransmitters gamma-aminobutyric acid ([(3)H]GABA) and dopamine ([(3)H]DA) was measured in both sets of cultures. [(3)H]GABA uptake, but not [(3)H]DA, was significantly increased in differentiated neurons in both neural stem cell cultures and bone marrow-derived cultures. [(3)H]GABA uptake was greater in differentiated neurons derived from brain neural stem cells. In summary, both the nestin-expressing bone marrow and the adult brain neural stem/progenitors developed into cells with morphological, immunocytochemical, and functional characteristics of neurons. Even though a smaller proportion of neuron-like cells was generated from bone marrow-derived progenitors than from brain-derived neural stem cells, these cells may be useful in the cellular therapy of neurodegenerative diseases and traumatic brain and spinal cord injury.     

Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.     

Adult neural stem cells from the mouse subventricular zone are limited in migratory ability compared to progenitor cells of similar origin

The subventricular zone (SVZ) in the forebrain is the largest source of neural stem cells and progenitor cells in the adult CNS. To assess the ability of adult neural stem cells to survive, differentiate and migrate, we have compared the behavior of dissociated, neurosphere-derived stem cells with that of progenitor cells in transplantation experiments. This ability was first tested in vivo, offering the stem cells the possibility to migrate along the rostral migratory stream (RMS), their specific pathway. In addition, the differential behaviors of the two classes of cells were also compared in vitro by grafting them into organotypic slice cultures containing either tangential (embryonic cerebral cortex) or radial (early postnatal cerebellar cortex) migratory routes. Most of the grafted adult neurosphere-derived stem cells survived and integrated in vivo, and a proportion of them differentiate into neurons, oligodendrocytes or astrocytes. However, they were unable to migrate along the RMS and remained in the vicinity of the injection site. In contrast, SVZ progenitor cells were able to migrate toward the olfactory bulb and, once there, to acquire the phenotype of granule cells, as previously reported. In vitro, neural stem cells exhibited a better migratory ability, although they only migrated for short distances, particularly, in forebrain slices. Nevertheless, the average distance covered by progenitor cells was a two-fold longer than that covered by neural stem cells, corroborating that this class of more specified cells has higher migratory ability. These results suggest that the in vitro conditions of expanding SVZ-derived stem cells, required to maintain them in an immature stage might modify their intrinsic properties, preventing their differentiation into neuroblasts and their subsequent migration.