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PubMed2001

High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain.

Neural stem and precursor cells reside in the ventricular lining of the fetal forebrain, and may provide a cellular substrate for brain repair. To selectively identify and extract these cells, we infected dissociated fetal human brain cells with adenoviruses bearing the gene for green fluorescence protein (GFP), placed under the control of enhancer/promoters for two genes (nestin and musashi1) that are expressed in uncommitted neuroepithelial cells. The cells were then sorted by fluorescence-activated cell sorting (FACS) on the basis of E/nestin- or P/musashi1-driven GFP expression. Both P/musashi1:hGFP- and E/nestin:EGFP-sorted cells were multipotent: limiting dilution with clonal expansion as neurospheres, in tandem with retroviral lineage analysis and xenograft to E17 and P0-2 rat forebrain, revealed that each phenotype was able to both self-renew and co-generate neurons and glia. Thus, fluorescent genes placed under the control of early neural promoters allow neural stem cells to be specifically targeted, isolated, and substantially enriched from the fetal human brain.

Adenoviridae↗
PubMed2005

Role of IL-6 in the neural stem cell differentiation.

In the developing brain neurons, astrocytes, and oligodendrocytes are differentiated from common multipotent progenitors called neural stem cells. We have examined the effect of cytokines on mouse neuroepithelial cells that are known to contain neural stem cells. Cytokines belonging to the interleukin (IL)-6 family and those classified into the bone morphogenetic protein (BMP) family act in synergy on neuroepithelial cells to induce astrocyte differentiation. Cooperation of these two types of cytokines is explained by the formulation of a complex between their respective downstream transcription factors (signal tranducer and activator of transcription [STAT]-3 and Smad1), bridged by a transcriptional coactivator (p300). Whereas BMPs family cytokines are involved in astrocyte differentiation, they inhibit neuronal differentiation. This appears to change the fate of neural progenitor cells from neurogenesis to astrocytogenesis. Interestingly, during brain development, neuronal differentiation starts at a very early stage and continues throughout development, whereas astrocytes appear just before term. We have shown that astrocyte differentiation is largely dependent on IL-6 family cytokine-mediated STAT3 activation and that there exists a STAT3 binding element in the promoter region of the gene for the astrocyte marker glial fibrillary acidic protein. A cytosine residue in this element is highly methylated in neuroepithelial cells in a mid-gestational stage but becomes demethylated in accordance with brain development. Because this methylation inhibits STAT3 binding, we suggest that DNA methylation is a critical determinant in the developmental stage-dependent regulation of astrocytogeneis. In conclusion, fate of neural stem cells during development is regulated by cell-intrinsic programs, such as epigenetic modification (including DNA methylation), and signaling crosstalk of cell-external mediators (including IL-6 family cytokines).

Animals↗
PubMed2004

Induction of GABAergic phenotype in a neural stem cell line for transplantation in an excitotoxic model of Huntington's disease.

The implementation of cell replacement therapies for Huntington's disease using multipotent neural stem cells (NSCs) requires the specific differentiation into gamma-aminobutyric acid (GABA) neuronal subtype before transplantation. Here we present an efficient culture procedure that induces stable GABAergic neurons from the immortalized striatal neural stem cell line ST14A. This process requires sequential retinoic acid treatment and KCl depolarization. Initial addition of 10 microM retinoic acid increased cell survival and promoted neuronal differentiation. Subsequent stimulation with 40 mM KCl induced specific differentiation into GABAergic neurons, yielding 74% of total cultured cells. KCl-evoked Ca(2+) influx reduced cell proliferation and nestin expression, and induced neurite outgrowth and GABAergic markers as well as GABA contents, release, and uptake. Characterization of the integration, survival, and phenotype of these predifferentiated GABAergic neurons following transplantation into the adult brain in a model of Huntington's disease revealed long-term survival in quinolinate-lesioned striata. Under these conditions, cells maintained their GABAergic phenotype and elaborated neurite processes with synaptic contacts with endogenous neurons. In conclusion, we have generated a homogeneous population of functional GABAergic neurons from a neural stem cell line, which survive and maintain their acquired fate in vivo. These data may lend support to the possibility of cell replacement therapies for Huntington's disease using neural stem cells.

Animals↗
PubMed2003

[Proliferation and differentiation of neural stem cells after cerebral infarction: an experimental study of adult rats].

OBJECTIVE: To investigate the proliferation and differentiation of neural stem cells after cerebral infarction(CI) in adult rats. METHODS: CI animal model was made by ligating the common carotid artery and external carotid artery and inserting a piece of nylon thread into the internal carotid artery among 100 male Wistar rats. Then the rats were randomly divided into 5 groups: group of I day after brain infarction (n = 20), group of 3 days after brain infarction (n = 20), group of 7 days after brain infarction (n = 20), group of 14 days after brain infarction (n = 20), and group of 28 days after brain infarction (n = 20). Twelve rats undergoing sham operation with a piece of nylon thread inserted only into the common carotid artery were used as controls. The rats were killed at different time points and their brains were taken out. The expression of bromodeoxyuridine (BrdU) and Musashil (both used to mark the dividing neural stem cells), and of glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN) (both used to mark the differentiating neural stem cells) were determined by immunohistochemistry and immunofluorescence staining. RESULTS: In the normal brain tissues, only a small amount of BrdU(+) cells were found in the hippocampus. One day after CI the number of BrdU(+) cells began to increase in the hippocampus at the CI side (P < 0.05), peaked 7 days after CI with a number 6 times that at the normal side, began to decrease 14 days after, and almost reached normal 28 days after. The number of BrdU(+)/Musashil(+) cells began to increase 1 day after CI (P < 0.05), peaked 7 days after, began to decrease 14 days after, and almost reached normal 28 days after. The number of BrdU(+)/GFAP(+) cells at the CI side remained almost unchanged after CI. The number of BrdU(+)/NeuN(+) cells began to increase 14 days after CI (P < 0.05) and peaked 38 days after. CONCLUSION: Cerebral infarction stimulates the proliferation of inherent neural stem cells and most proliferated neural stem cells differentiate into neurons.

Animals↗
PubMed2005

Visualization of embryonic neural stem cells using Hes promoters in transgenic mice.

In the central nervous system, neural stem cells proliferate in the ventricular zone (VZ) and sequentially give rise to both neurons and glial cells in a temporally and spatially regulated manner, suggesting that stem cells may differ from one another in different brain regions and at different developmental stages. For the purpose of marking and purifying neural stem cells to ascertain whether such differences exist, we generated transgenic mice using promoters from Hes genes (pHes1 or pHes5) to drive expression of destabilized enhanced green fluorescent protein. In the developing brains of these transgenic mice, GFP expression was restricted to undifferentiated cells in the VZ, which could asymmetrically produce a Numb-positive neuronal daughter and a GFP-positive progenitor cell in clonal culture, indicating that they retain the capacity to self-renew. Our results suggest that pHes-EGFP transgenic mice can be used to explore similarities and differences among neural stem cells during development.

Animals↗
PubMed2005

19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain.

Abuse of androgenic anabolic steroids can affect brain function leading to behavioural changes. In this study, the effects of the testosterone analogue, 19-nortestosterone, on rat neural stem cells was examined. The androgen receptor is expressed by cultured embryonic and adult neural stem cells, and is also present in the ventricular epithelium during development and in the adult brain in, among others, dentate gyrus. In neural stem cells stimulated with epidermal growth factor, nandrolone reduced cell proliferation, especially in adult ones. The decrease was abolished by flutamide, a receptor antagonist. Nandrolone also decreased the BrdU labelling of neural stem cells in the dentate gyrus, demonstrating an effect of the hormone on cell proliferation in vivo. The effect of nandrolone was observed with both female and male rats but it was more pronounced in pregnant rats, indicating an involvement of oestrogen in nandrolone action. Nandrolone also decreased the number of newly born neuronal cells in the dentate gyrus of male rats. The results show that nandrolone has important effects on the proliferation and differentiation of neural stem cells expressing the cognate androgen receptor. The data show that the use of nandrolone may severely affect the formation of neural stem cells and could therefore have long-term negative consequences in the brain.

Age Factors↗
PubMed2002

Transplantation of an indigenous neural stem cell population leading to hyperplasia and atypical integration.

Astrocytes exhibit neural stem cell characteristics in vitro by generating multipotent clones of cells. In order to see if normal cues are present in vivo that can direct these astrocytes to generate cells of neuronal lineage, the astrocytes were transplanted into the persistently neurogenic mouse subependymal zone/rostral migratory stream. Grafted astrocytes assumed migratory profiles, joined chains of indigenous neuroblasts, and migrated into the olfactory bulb. Additionally, however, some grafted astrocytes "homed" to the lateral ventricle where they became hyperplastic, forming spherical structures composed of cells of mixed phenotype that attached to the ventricular wall, and eventually penetrated and dispersed within surrounding brain parenchyma. It is proposed that, with an interest in the use of stem cell transplants for neurological disease, findings of hyperplasia and apparent atypical integration of a native population of multipotent astrocytic stem cells suggest the need for caution before beginning even autologous neural stem cell transplants.

Animals↗
PubMed2004

[Transplantation of gene-transfected neural stem cells for transient cerebral ischemia in rats].

OBJECTIVE: To detect the expression and the role of vascular endothelial growth factor (VEGF)-transfected neural stem cells (NSCs) in rat brain subjected to ischemia. METHODS: Fetal NSCs were cultured from E14 days SD rats and transfected with VEGF121 gene by using lipofectAMINE technique. The gene expression of transfected cells was detected by RT-PCR and immunofluorescent staining in vitro. Temporary middle cerebral artery occlusion (tMCAO) model was established in 40 SD rats and then rate were randomly divided into (1) control group (n = 10), (2) PBS transplantation group (n = 10), (3) neural stem cells transplantation group (n = 10), and (4) VEGF-secreting neural stem cells transplantation group (n = 10). BrdU-labelled NSCs and VEGF-secreting NSCs were transplanted into the penumbra zones respectively 3 days after the tMCAO model was established. Neurological Severity Score (NSS) was checked in all groups 2, 4, 6, 8, 10, 12 weeks respectively after transplantation. One and 12 weeks after the transplantation, 10 rats in the group (4) were killed and then brains taken out respectively. By using immunofluorescent staining, the VEGF expression of transplanted cells 1 week after transplantation, differentiation and migration of transplanted neural stem cells 12 week after transplantation were detected respectively. RESULTS: VEGF-transfected neural stem cells could continuously express gene products during the first 2 weeks. Both transfected NSCs and their progeny expressed VEGF gene products, which was demonstrated by fluorescence study. There were no significant differences in NSS in groups 4 when tMCAO models were just established. However, the values of NSS in (4) group were 5.8 +/- 1.5, 5.0 +/- 1.0, 4.6 +/- 1.0, 4.0 +/- 0.7, 4.0 +/- 1.0, 3.8 +/- 0.4 from 2 approximately 12 weeks after transplantation, significantly lower than those in groups (1) and (2) 8 weeks (P = 0.008) and those in groups (1), (2) and (3) 12 weeks (P = 0.000) after transplantation. NSS in group (3) was also lower than that in groups (1) and (2) 8 and 12 weeks after transplantation. One week after transplantation, immunofluorescent staining showed that VEGF-transfected NSCs migrated and expressed VEGF into hosts' brains. Twelve weeks after transplantation, transplanted NSCs survived and migrated, some of them differentiated to neurons and integrated well with hosts' cytoarchitectural components. CONCLUSION: VEGF-transfected NSCs express gene products during the early time after transplantation, which reduce brain injury through protecting the vascular system against ischemia and reperfusion injury. Transplantation of VEGF-transfected NSCs might be a novel method for treatment of cerebral ischemia.

Animals↗
PubMed2006

Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells.

To investigate the effects of suppressors of cytokine signaling 3 (SOCS3) on neural stem cell fate, stem cells were infected with an adenoviral vector expressing SOCS3. Three days later, western blot analysis and immunocytochemical analysis revealed that the protein level of MAP2 and the number of MAP2-positive cells were significantly increased in SOCS3-transfected cells, whereas the protein level of GFAP and the number of GFAP-positive cells were significantly decreased. Furthermore, promoter assay revealed a significant reduction in the transcriptional level of signal transducer and activator of transcription 3 (Stat3) in the transfected cells. In addition, the mRNA levels of Notch family member (notch1) and inhibitory basic helix-loop-helix (bHLH) factors (hes5 and id3) were significantly up-regulated 1 day after overexpression of SOCS3. Three days after transfection, the mRNA level of hes5 was significantly decreased, whereas that of notch1 was still up-regulated. Moreover, all of SOCS3-positive cells expressed Nestin protein but did not express MAP2 or GFAP proteins. These data indicate that overexpression of SOCS3 induced neurogenesis and inhibited astrogliogenesis in neural stem cells. Our data also show that SOCS3 promoted maintenance of neural stem cells.

Adenoviridae↗
PubMed2005

Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways.

Bmi-1 is required for the post-natal maintenance of stem cells in multiple tissues including the central nervous system (CNS) and peripheral nervous system (PNS). Deletion of Ink4a or Arf from Bmi-1(-/-) mice partially rescued stem cell self-renewal and stem cell frequency in the CNS and PNS, as well as forebrain proliferation and gut neurogenesis. Arf deficiency, but not Ink4a deficiency, partially rescued cerebellum development, demonstrating regional differences in the sensitivity of progenitors to p16Ink4a and p19Arf. Deletion of both Ink4a and Arf did not affect the growth or survival of Bmi-1(-/-) mice or completely rescue neural development. Bmi-1 thus prevents the premature senescence of neural stem cells by repressing Ink4a and Arf, but additional pathways must also function downstream of Bmi-1.

Animals↗
PubMed2004

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.

Analysis of Variance↗
PubMed2001

Induction of highly polysialylated neural cell adhesion molecule (PSA-NCAM) in postischemic gerbil hippocampus mainly dissociated with neural stem cell proliferation.

We investigated a possible expression of highly polysialylated neural cell adhesion molecule (PSA-NCAM) in gerbil hippocampus after 5 min of transient global ischemia in association to the proliferation of neural stem cell labeled with bromodeoxyuridine (BrdU). The number of PSA-NCAM positive cells increased in the granule cell layer (GCL) of dentate gyrus (DG) by 1.9 to 2.7-fold at 10 and 20 days after the reperfusion. The number of BrdU-labeled cells increased mainly in the subgranular zone of DG by 7.2 to 8.0-fold at 5 and 10 days after the reperfusion. Immunofluorescence for PSA-NCAM and BrdU showed that the majority of DG cells were not double labeled, while one or two cells per section were double labeled in the deepest portion of the GCL only at 10 days after the reperfusion. These results suggest different predominant spatial distribution and chronological change of PSA-NCAM positive and BrdU-labeled cells in DG after transient ischemia.

Animals↗
PubMed2003

Effect of rat Schwann cell secretion on proliferation and differentiation of human neural stem cells.

OBJECTIVE: To investigate the effect of rat Schwann cell secretion on the proliferation and differentiation of human embryonic neural stem cells (NSCs). METHODS: The samples were divided into three groups. In Group One, NSCs were cultured in DMED/F12 in which Schwann cells had grown for one day. In Group Two, NSCs and Schwann cells were co-cultured. In Group Three, NSCs were cultured in DMEM/F12. The morphology of NSCs was checked and beta-tubulin, GalC, hoechst 33342 and GFAP labellings were detected. RESULTS: In Group One, all neural spheres were attached to the bottom and differentiated. The majority of them were beta-tubulin positive while a few of cells were GFAP or GalC positive. In Group Two, neural spheres remained undifferentiated and their proliferation was inhibited in places where Schwann cells were robust. In places where there were few Schwann cells, NSCs performed in a similar manner as in Group One. In Group Three, the cell growth state deteriorated day after day. On the 7th day, most NSCs died. CONCLUSION: The secretion of rat Schwann cells has a growth supportive and differentiation-inducing effect on human NSCs.

Animals↗
PubMed2005

Human cord blood-derived neural stem cell line--possible implementation in studying neurotoxicity.

Neural stem cell line developed from human umbilical cord blood (HUCB-NSC) [Buzańska et al., 2003. Journal of Neurochemistry 85, 33] is an ethically uncontroversial source of stem cells, able to differentiate into neuronal, astrocytic and oligodendroglial lineages. Developmental fate decisions of HUCB-NSC can be experimentally manipulated in vitro by the presence of trophic factors, mitogenes and neuromorphogenes, but can also be influenced by neurotoxins. In this report two-dimensional (2-D) and three-dimensional (3-D) HUCB-NSC cultures are introduced as useful models for testing developmental neurotoxicity. For 2-D culture models we established a standardized method for the assessment of the growth rate and cell differentiation in 96-well plates. The proliferative capacity of the HUCB-NSC was monitored by the MTT test while their ability to differentiate into neural-like cells by immunocytochemistry of beta-tubulin III and MAP-2 for neurons, GFAP and S-100beta for astrocytes and GalC for oligodendrocytes. The 3-D culture of HUCB-NSC is represented by neurospheres. Proliferation and migration of the intermediate precursors from attached neurospheres are shown to be controlled and altered by various growth factors and further modulated by the extracellular matrix component-fibronectin. Thus, neurospheres derived from the HUCB-NSC line can represent a suitable model of the activation of dormant stem cells residing in their niche, and can be used for neurotoxic studies.

Astrocytes↗
PubMed2006

The therapeutic potential of neural stem cells.

Recent evidence shows that transplantation of neural stem/precursor cells may protect the central nervous system from inflammatory damage through a 'bystander' mechanism that is alternative to cell replacement. This novel mechanism, which might improve the success of transplantation procedures, is exerted by undifferentiated neural stem cells, the functional characteristics of which are regulated by important stem cell regulators released by CNS-resident and blood-borne inflammatory cells. Here, we discuss this alternative bystander mechanism in the context of the atypical ectopic perivascular niche. We propose that it is the most challenging example of reciprocal therapeutic crosstalk between the inflamed CNS and systemically transplanted neural stem cells.

Animals↗
PubMed2004

[Isolation, culture and identification of rat hippocampal neural stem cells].

OBJECTIVE: To explore the feasibility of the isolation, culture and identification of the neural stem cells originated from the hippocampi of neonatal rats (1-3 d) and adult rats respectively. METHODS: The neural stem cells were isolated from the hippocampi of neonatal and adult rats and cultured in serum-free medium containing basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF) and other growth factors using single-cell cloning technique. Immunochemistry was employed to identify the cloned cells and their daughter cells as well as mature neural cells differentiated from the cell clone. RESULTS: The floating neural spheres obtained by above culture procedures for isolated cells from the hippocampi of neonatal and adult rats were positive for nestin expression, with the potential for further cloning and capable of differentiation into neurons or glial cells, which formed reticular connection between the cells and expressed neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) respectively. CONCLUSION: The hippocampi of neonatal and adult rats contain neural stem cells.

Animals↗
PubMed1998

Neural stem cells: from fly to vertebrates.

Our goal in this review is to explore the relationship between Drosophila and vertebrate neural stem cell development by comparing progress in each system with the aim of answering several central questions in stem cell biology: (a) How are stem cells formed? (b) Do stem cells divide symmetrically or asymmetrically? (c) How is stem cell fate maintained? (d) How is stem cell differentiation initiated? (e) How are different stem cell fates determined? (f) How "plastic" are different neural stem cell fates? (g) How do neural stem cells produce different progeny? and (h) What regulates stem cell proliferation versus quiescence? Not surprisingly, research in Drosophila and vertebrate systems each have their own biases, strengths, and weaknesses; we hope that by directly comparing progress in each field, new experiments and interpretations in both vertebrate and Drosophila research will become apparent. It has become increasingly clear that vertebrates and Drosophila share many fundamental mechanisms of neurogenesis, validating a comparative approach.

Animals↗
PubMed2006

High susceptibility of neural stem cells to methylmercury toxicity: effects on cell survival and neuronal differentiation.

Neural stem cells (NSCs) play an essential role in both the developing embryonic nervous system through to adulthood where the capacity for self-renewal may be important for normal function of the CNS, such as in learning, memory and response to injury. There has been much excitement about the possibility of transplantation of NSCs to replace damaged or lost neurones, or by recruitment of endogenous precursors. However, before the full potential of NSCs can be realized, it is essential to understand the physiological pathways that control their proliferation and differentiation, as well as the influence of extrinsic factors on these processes. In the present study we used the NSC line C17.2 and primary embryonic cortical NSCs (cNSCs) to investigate the effects of the environmental contaminant methylmercury (MeHg) on survival and differentiation of NSCs. The results show that NSCs, in particular cNSCs, are highly sensitive to MeHg. MeHg induced apoptosis in both models via Bax activation, cytochrome c translocation, and caspase and calpain activation. Remarkably, exposure to MeHg at concentrations comparable to the current developmental exposure (via cord blood) of the general population in many countries inhibited spontaneous neuronal differentiation of NSCs. Our studies also identified the intracellular pathway leading to MeHg-induced apoptosis, and indicate that NSCs are more sensitive than differentiated neurones or glia to MeHg-induced cytotoxicity. The observed effects of MeHg on NSC differentiation offer new perspectives for evaluating the biological significance of MeHg exposure at low levels.

Animals↗