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PubMed2005

Quantitative analysis of gene expression in living adult neural stem cells by gene trapping.

The potential of neural stem cells (NSCs) for the treatment of neurodegenerative diseases makes the identification and characterization of genes involved in neural stem cell responses therapeutically important. Although technologies exist for measuring gene expression in cells, they often provide only a representative expression profile specific to a stimulus and time. We developed a complementary technology based on a retroviral-vector gene-trap approach that uses beta-lactamase-induced disruption of fluorescence resonance energy transfer in the fluorophore CCF-2/AM. A library of 'tagged' adult rat NSCs was generated by transduction with gene-trap virus produced from a single-integrant packaging cell line that allowed us to quantitatively analyze dynamic gene expression changes in real time in living NSCs. Using this library we identified previously unknown genes regulated by oxidative stress, indomethacin and factors that induce differentiation, and show that one of the trapped genes, Sox6, is sufficient to induce astrocytic differentiation when overexpressed.

Animals↗
PubMed2005

Glial influences on neural stem cell development: cellular niches for adult neurogenesis.

Neural stem cells continually generate new neurons in very limited regions of the adult mammalian central nervous system. In the neurogenic regions there are unique and highly specialized microenvironments (niches) that tightly regulate the neuronal development of adult neural stem cells. Emerging evidence suggests that glia, particularly astrocytes, have key roles in controlling multiple steps of adult neurogenesis within the niches, from proliferation and fate specification of neural progenitors to migration and integration of the neuronal progeny into pre-existing neuronal circuits in the adult brain. Identification of specific niche signals that regulate these sequential steps during adult neurogenesis might lead to strategies to induce functional neurogenesis in other brain regions after injury or degenerative neurological diseases.

Animals↗
PubMed2006

Proliferation and differentiation of adult endogenous neural stem cells in response to neurodegenerative process within the striatum.

The ongoing process of neurogenesis in the adult mammalian forebrain suggests the possible capacity for limited self-repair after brain injury. Previously, we have demonstrated that in an animal model of Huntington's disease the neurodegenerative process initiates immediate intensive cell proliferation and differentiation resulting in characteristic enlargement of the subependymal zone (SEZ) of lateral brain ventricles. Now, our interest is focused on the architecture of the neurogenic niche of the SEZ in the identical model, particularly on characteristic features of astrocyte-like cells which are considered to be not only niche cells but also neural stem cells. Our findings prove higher activation of the lateral part of the SEZ (L-SEZ) adjacent to the degenerated striatum compared with the rostral part of the SEZ (R-SEZ). In the activated L-SEZ, niche cells which ensheathe clusters of neural progenitors are of immature astrocytic phenotype because of nestin and vimentin expression (except the expression of glial fibrillary acidic protein). However, the coexpression of all three filaments is not always found. Intermediate filaments also enable us to distinguish the basic shape of astrocytic cells within the SEZ, majority of which resemble protoplasmic rather than fibrillary astrocytes. Furthermore, our results show a wide plasticity of these astrocyte-like cells in immediate response to an extensive pathological process in the brain. These observations are consistent with the fact that adult stem cells undergo different processes in an already mature environment, and therefore can exhibit some specific characteristics unlike the embryonic or fetal neural stem cells.

Adult↗
PubMed2003

The human NTERA2 neural cell line generates neurons on growth under neural stem cell conditions and exhibits characteristics of radial glial cells.

NTERA2 cells are a human neural cell line generating neurons after exposure to retinoic acid and, as such, are widely used as a model of neurogenesis. We report that these cells form spheres when grown in serum-free medium supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). These spheres were found to express markers of radial glial cells such as, Pax6, glutamate transporter (GLAST), tenascin C, brain lipid-binding protein (BLBP), and the 3CB2 antigen. On plating on an adhesive substrate, NTERA2 spheres generate a large percentage of immature neurons (30-50%) together with a minority of cells of the oligodendrocyte lineage. Thus NTERA2 cells share properties with neural stem cells. However, at variance with the latter, we found that they produce their own bFGF implicated in an autocrine or paracrine proliferative loop and that they do not generate astrocytes after differentiation. These results provide an interesting model to study radial glial cells and their role in human neurogenesis.

Animals↗
PubMed2003

Long-term cultivation of multipotential neural stem cells from adult rat subependyma.

Cultivation of adult rat neural stem cells (RNSCs) from the ventricular subependyma has been reported to be more difficult than growth of mouse neural stem cells. This is unfortunate, because rats provide useful models of brain function and disease, and implantation of RNSCs in these models could provide critical information on allograft behavior. Growing the cells in an appropriate medium (NS-A+B27 supplement), plating at sufficient densities (>5 cells per mm(2)), and minimizing opportunities for detachment from the substratum made it possible to isolate and cultivate these cells for over 6 months for >50 passages with no apparent change in phenotype. Single clones could be expanded indefinitely and differentiated to form astrocytes, oligodendrocytes, and neurons, demonstrating that the cultures did indeed contain neural stem cells. The cells had a much shorter cell cycle time ( approximately 13 h) than doubling time ( approximately 35 h), suggesting that these cells produce post-mitotic cells in approximately two of three divisions, thus making expansion difficult. The optimization of methods to grow adult RNSCs and identification of characteristics that limit their growth should prove useful in increasing the use of RNSCs for studies of their potential role in brain health and disease.

Animals↗
PubMed2004

Possible oncogenicity of subventricular zone neural stem cells: case report.

OBJECTIVE: The origin of brain tumors has attracted much controversy. Recent advances in neural stem cell biology coupled with the new concepts of central nervous system development have raised interesting possibilities regarding the oncogenic properties of neural stem/progenitor cells. To elucidate these putative properties further, the clinical materials from an infant brain tumor were analyzed, focusing on the relation with the neural stem/progenitor cells. METHODS: The expression of neural stem/progenitor cell markers in the tumor cells and the cellular components of the infant brain tumor were examined using immunohistochemistry. The tumor cell biology was analyzed both in culture and in the grafted brain environment. RESULTS: Three main bodies of evidence were demonstrated indicating that the tumor was of possible subventricular zone postnatal or adult normal neural stem cell origin. First, in the tumor specimen we demonstrated the strong positive expression of the neural stem/progenitor cell markers, nestin and Musashi-1. Second, immunohistochemistry revealed the presence of neuronal, astrocytic, and immature precursor cells in the tumor tissue, similar to the cellular components of the subventricular zone, thereby pointing to the subventricular zone as the possible origin of the tumor. The subventricular zone also is one of the strong candidates for the location of postnatal/adult neural stem cells. This cellular evidence was strengthened further by the clinicoradiological findings that demonstrated the involvement of the subventricular zone of the lateral ventricle by the tumor. Third, in the in vitro and in vivo experiments, a dynamic shift in expression patterns between neural stem cells (nestin, Musashi-1) and differentiated cells (glial fibrillary acidic protein, neuron-specific Class III beta-tubulin) markers was seen, similar to the proposed behavior of postnatal/adult neural stem cells in situ. CONCLUSION: These findings suggest that this brain tumor originated from neural stem cells located in the subventricular zone, and the further possibility of the general oncogenic potential of neural stem cells.

Brain Neoplasms↗
PubMed2003

The proteome of neural stem cells from adult rat hippocampus.

BACKGROUND: Hippocampal neural stem cells (HNSC) play an important role in cerebral plasticity in the adult brain and may contribute to tissue repair in neurological disease. To describe their biological potential with regard to plasticity, proliferation, or differentiation, it is important to know the cellular composition of their proteins, subsumed by the term proteome. RESULTS: Here, we present for the first time a proteomic database for HNSC isolated from the brains of adult rats and cultured for 10 weeks. Cytosolic proteins were extracted and subjected to two-dimensional gel electrophoresis followed by protein identification through mass spectrometry, database search, and gel matching. We could map about 1141 PlusMinus; 209 (N = 5) protein spots for each gel, of which 266 could be identified. We could group the identified proteins into several functional categories including metabolism, protein folding, energy metabolism and cellular respiration, as well as cytoskeleton, Ca2+ signaling pathways, cell cycle regulation, proteasome and protein degradation. We also found proteins belonging to detoxification, neurotransmitter metabolism, intracellular signaling pathways, and regulation of DNA transcription and RNA processing. CONCLUSIONS: The HNSC proteome database is a useful inventory which will allow to specify changes in the cellular protein expression pattern due to specific activated or suppressed pathways during differentiation or proliferation of neural stem cells. Several proteins could be identified in the HNSC proteome which are related to differentiation and plasticity, indicating activated functional pathways. Moreover, we found a protein for which no expression has been described in brain cells before.

Journal Article↗
PubMed2000

Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS.

The ready availability of unlimited quantities of neural stem cells derived from the human brain holds great interest for basic and applied neuroscience, including therapeutic cell replacement and gene transfer following transplantation. We report here the combination of epigenetic and genetic procedures for perpetuating human neural stem cell lines. Thus we tested various culture conditions and genes for those that optimally allow for the continuous, rapid expansion and passaging of human neural stem cells. Among them, v-myc (the p110 gag-myc fusion protein derived from the avian retroviral genome) seems to be the most effective gene; we have also identified a strict requirement for the presence of mitogens (FGF-2 and EGF) in the growth medium, in effect constituting a conditional perpetuality or immortalization. A monoclonal, nestin-positive, human neural stem cell line (HNSC.100) perpetuated in this way divides every 40 h and stops dividing upon mitogen removal, undergoing spontaneous morphological differentiation and upregulating markers of the three fundamental lineages in the CNS (neurons, astrocytes, and oligodendrocytes). HNSC.100 cells therefore retain basic features of epigenetically expanded human neural stem cells. Clonal analysis confirmed the stability, multipotency, and self-renewability of the cell line. Finally, HNSC.100 can be transfected and transduced using a variety of procedures and genes encoding proteins for marking purposes and of therapeutic interest (e.g., human tyrosine hydroxylase I).

Blotting, Southern↗
PubMed2004

[Expression of Notch1 gene in the differentiation of the human embryonic neural stem cells to neurons].

AIM: To explore the expression and role of Notch1 gene in the differentiation of the human embryonic neural stem cells to neurons induced by all-trans-retinoic-acid(ATRA). METHODS: The human embryonic neural stem cells were induced with various concentrations of ATRA(0.5, 1, 5 and 10 mumol/L) in vitro. Immunofluorescence staining was performed after seven days, and neurons were quantified by counting NSE positive cells. Then human embryonic neural stem cells were induced to differentiate with 1 mumol/L ATRA. Total RNA was extracted from the cells before inducing, induced for 3 days, and for 7 days. The expression of Notch1 gene was tested by semi-quantitative RT-PCR. RESULTS: The ratio of neural stem cells to differentiate to neurons was improved greatly by ATRA induction as compared with control group (P<0.01). 1 mumol/L ATRA was the optimal dose for induction of the human embryonic neural stem cell differentiation. The percentage of neurons induced by 1 micromol/L ATRA was (29.20+/-1.09)%. The expression of Notch1 gene decreased significantly after being treated with ATRA(P<0.001). CONCLUSION: ATRA can greatly increase the percentage of neurons in the course of inducing the human embryonic neural stem cells to differentiate. Notch1 gene is down-regulated when human embryonic neural stem cells differentiate into neurons.

Brain↗
PubMed2005

Recombinant adenovirus-mediated vascular endothelial growth factor gene transfer attenuates hypoxia-induced apoptosis of neural stem cells in vitro.

OBJECTIVE: To study the effects of vascular endothelial growth factor (VEGF) gene transfer on hypoxia-induced apoptosis of neural stem cells in vitro. METHODS: C17.2 neural stem cells cultured in vitro were infected by recombinant adenovirus containing VEGF gene and cultured under hypoxic condition. VEGF expression in these cells was detected by Western blotting, and the apoptotic index was calculated from results of triphosphate-biotin nick end-labeling (TUNEL) assay. Flow cytometry was employed to examine the changes in the cell apoptotic rate after VEGF gene transfer, and the apoptotic bodies were observed under fluorescence microscope with Hoechst33342 staining. RESULTS: The expression of VEGF was significantly increased in pAdCMV VEGF(165)-infected cells, resulting in inhibition of the apoptosis of C17.2 neural stem cells induced by hypoxia manifested by a significantly lower apoptotic rate of the stem cells transfected by pAdCMV VEGF(165) than that of the untransfected cells (10.38%;+/-0.48%; vs 19.98 %;+/-0.55%;, P<0.01) and of the cells transfected with pAdCMV VEGF(165) along with VEGF anti-sense oligodeoxynucleotide (19.07%;+/-0.64%;, <0.01) after hypoxia. CONCLUSIONS: Recombinant adenovirus can efficiently mediate VEGF gene transfer into C17.2 neural stem cells, resulting in high expression of the exogenous VEGF in vitro, which effectively reduces C17.2 neural stem cell apoptosis induced by hypoxia.

Adenoviridae↗
PubMed2006

D609 blocks cell survival and induces apoptosis in neural stem cells.

In order to investigate the effects of tricyclodecane-9-yl-xanthogenate (D609) on the survival of neural stem cells (NSCs), which were isolated from rat forebrain, we treated the NSCs with D609 in the presence of basic fibroblast growth factor (bFGF). We found that when NSCs were exposed to 18.76-56.29 microM D609, the viability of the cells remarkably declined and apoptosis occurred. At the same time, the ROS level in NSCs was depressed. The data suggested that D609 was a powerful growth inhibitor and apoptosis inducer in NSCs.

Animals↗
PubMed2002

Neural stem cells and neurodegeneration.

Neurodegenerative diseases, such as Parkinson's disease, are characterized by a continuous loss of specific populations of neurons. Possible regenerative interventions include transplanting developing neural tissue or neural stem cells into the host brain, and inducing proliferation of endogenous stem cells by pharmacological manipulations. Neural stem cells (NSC), with the capacity to self-renew and produce the major cell types of the brain, exist in the developing and adult central nervous system (CNS). These cells can be grown in vitro while retaining the potential to differentiate into nervous tissue. This review focuses on regenerative therapy in neurodegenerative diseases using NSC.

Animals↗
PubMed2004

Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway.

Migration toward pathology is the first critical step in stem cell engagement during regeneration. Neural stem cells (NSCs) migrate through the parenchyma along nonstereotypical routes in a precise directed manner across great distances to injury sites in the CNS, where they might engage niches harboring local transiently expressed reparative signals. The molecular mechanisms for NSC mobilization have not been identified. Because NSCs seem to home similarly to pathologic sites derived from disparate etiologies, we hypothesized that the inflammatory response itself, a characteristic common to all, guides the behavior of potentially reparative cells. As proof of concept, we show that human NSCs migrate in vivo (including from the contralateral hemisphere) toward an infarcted area (a representative CNS injury), where local astrocytes and endothelium up-regulate the inflammatory chemoattractant stromal cell-derived factor 1alpha (SDF-1alpha). NSCs express CXC chemokine receptor 4 (CXCR4), the cognate receptor for SDF-1alpha. Exposure of SDF-1alpha to quiescent NSCs enhances proliferation, promotes chain migration and transmigration, and activates intracellular molecular pathways mediating engagement. CXCR4 blockade abrogates their pathology-directed chain migration, a developmentally relevant mode of tangential migration that, if recapitulated, could explain homing along nonstereotypical paths. Our data implicate SDF-1alpha/CXCR4, representative of the inflammatory milieu characterizing many pathologies, as a pathway that activates NSC molecular programs during injury and suggest that inflammation may be viewed not simply as playing an adverse role but also as providing stimuli that recruit cells with a regenerative homeostasis-promoting capacity. CXCR4 expression within germinal zones suggests that NSC homing after injury and migration during development may invoke similar mechanisms.

Animals↗
PubMed2004

Proliferation and differentiation of neural stem cells in adult rats after cerebral infarction.

OBJECTIVE: To investigate proliferation and differentiation of neural stem cells in adult rats after cerebral infarction. METHODS: Models of cerebral infarction in rats were made and the time-course expression of bromodeoxyuridine (BrdU), Musashi1, glial fibrillary acidic protein (GFAP), and neuronal nuclear antigen (NeuN) were determined by immunohistochemistry and immunofluorescence staining. BrdU and Musashi1 were used to mark dividing neural stem cells. GFAP and NeuN were used to mark differentiating neural stem cells. RESULTS: Compared with controls, the number of BrdU-labeled and BrdU-labeled with Musashi 1-positive cells increased strikingly 1 day after cerebral infarction; approximately 6 fold with a peak 7 days later; markedly decreased 14 days later, but was still elevated compared with that of controls; decling to the control level 28 days later. The number of BrdU-labeled with GFAP-positive cells nearly remained unchanged in the hippocampus after cerebral infarction. The number of BrdU-labeled with NeuN-positive cells increased strikingly 14 days after cerebral infarction, reached maximum peak in the hippocampus 28 days after cerebral infarction in rats. CONCLUSION: Cerebral infarction stimulate proliferation of inherent neural stem cells and most proliferated neural stem cells differentiate into neurons.

Animals↗
PubMed2005

The controlled differentiation of human neural stem cells into TH-immunoreactive (ir) neurons in vitro.

The expansion of human neural stem cells in vitro might overcome the poor donor supply of human fetal neural tissue in transplantation for Parkinson's disease. However, the differentiation of human neural stem cells into dopaminergic neurons has proven difficult. In the present study, we investigated the effects of cytokines, trophic factors of developmental striatum and Ginkgolide on differentiation of human neural stem cells (hNSCs) into TH-ir neurons. The immunoreactivity to tyrosine hydroxylase (TH), a distinctive marker for dopamine neurons was used to assess dopaminergic neuronal phenotype. We demonstrate that human neural stem cells expanded in vitro can efficiently differentiate into TH-ir neurons by induction. These stem cells might serve as a continuous, on-demand source of cells for therapeutic transplantation in patients with Parkinson's disease.

Animals↗
PubMed2004

Muscarinic acetylcholine receptors involved in the regulation of neural stem cell proliferation and differentiation in vitro.

Neural stem cells (NSCs) are currently considered powerful candidates for cell therapy in neurodegenerative disorders such as Parkinson's disease. However, it is not known when and how NSCs begin to differentiate functionally. Recent reports suggest that classical neurotransmitters such as acetylcholine (Ach) are involved in the proliferation and differentiation of neural progenitor cells, suggesting that neurotransmitters play an important regulatory role in development of the central nervous system (CNS). We have shown by calcium imaging and immunochemistry that proliferation and differentiation are enhanced by M2 muscarinic Ach receptors (mAchR) expressed on the NSC surface and on their neural progeny. Moreover, atropine, an mAchR antagonist, blocks the enhancement and inhibits the subsequent differentiation of NSCs. Further understanding of this neural-nutrition role of Ach might elucidate fetal brain development, the brain's response to injury, and learning and memory.

Animals↗
PubMed2006

Neural stem cells: isolation and differentiation into cholinergic neurons.

This investigation aimed to isolate neural stem cells from neonatal hippocampus and induce them to differentiate into cholinergic neurons. The isolated neural stem cells were incubated in serum-free Dulbecco's modified Eagle medium/F12 medium added with 20 ng/ml basic fibroblast growth factor and B27. The cell line isolated from the hippocampal formation of neonatal rats expressed nestin and had the potency to form clones and differentiate into neurons, astrocytes and oligodendrocytes. Embryonic chick skeletal muscle extract was used to induce the differentiation of the neural stem cells into cholinergic neurons. Immunocytochemistry was used to detect the choline acetyltransferase antigen of cholinergic neurons for confirmation. The results showed that embryonic chick skeletal muscle extract could induce isolated neural stem cell to differentiate into a significantly larger number of cholinergic neurons than controls.

Animals↗
PubMed2003

[Is the brain a postmitotic organ? -- current knowledge on neural stem cells].

All the attempts for regeneration in the central nervous system (in clinical conditions) are still a failure. Hence the bulk of clinicists are convinced that the brain is a postmitotic organ. Are the pessimists right? In the recent few years some knowledge break-throughs have been made. It has been noticed in many places of adult mammals' brains there are cells capable of proliferating, including asymmetric divisions, and differentiating into neurons and glia when suitably stimulated. Such cells, called neural stem cells, are present also in the brains of adult humans, especially in the subventricular zone. It has been recently discovered that also cells derived from bone marrow are capable of differentiating into neurons. The authors reviewed world-wide literature devoted to this topic. They focused mainly on the biology of the newly discovered cells, and especially on their mitotic and differentiating potential. The authors critically assess the discoveries discussed.

Brain↗