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PubMed2004

Comprehensive proteome expression profiling of undifferentiated versus differentiated neural stem cells from adult rat hippocampus.

Adult neural stem cells can be isolated from various regions of the rat brain and seem to have multilineage differentiation potential. In this study, we investigated the hypothesis that global protein expression of adult neural stem cells isolated from rat hippocampus is changed during in vitro differentiation. After 2 days of differentiation, we separated total protein extracts by two-dimensional gel electrophoresis and used mass spectrometry and gel-matching for identification. We detected a differential expression in 367 regulated protein spots, of which 128 could be identified. Regulated proteins included participants in transcription and DNA metabolism; signal transduction and Ca2+-signaling; MAP kinase pathways; cytoskeletal rearrangement; regulation of cell cycle, proliferation, and survival; protein biosynthesis, folding, and degradation; and glycine and glutamate metabolic pathways. These results suggest a massive reorganization of the stem cell proteomic profile upon differentiation and indicate potential cellular targets mediating the differentiation of neural stem cells.

Animals↗
PubMed2005

Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice.

Stem/progenitor cells from bone marrow and other sources have been shown to repair injured tissues by differentiating into tissue-specific phenotypes, by secreting chemokines, and, in part, by cell fusion. Here we prepared the stem/progenitor cells from human bone marrow (MSCs) and implanted athem into the dentate gyrus of the hippocampus of immunodeficient mice. The implanted human MSCs markedly increased the proliferation of endogenous neural stem cells that expressed the stem cell marker Sox2. Labeling of the mice with BrdUrd demonstrated that, 7 days after implantation of the human MSCs, BrdUrd-labeled endogenous cells migrated throughout the dorsal hippocampus (positive for doublecortin) and expressed markers for astrocytes and for neural or oligodendrocyte progenitors. Subpopulations of BrdUrd-labeled cells exhibited short cytoplasmic processes immunoreactive for nerve growth factor and VEGF. By 30 days after implantation, the newly generated cells expressed markers for more mature neurons and astrocytes. Also, subpopulations of BrdUrd-labeled cells exhibited elaborate processes immunoreactive for ciliary neurotrophic factor, neurotrophin-4/5, nerve growth factor, or VEGF. Therefore, implantation of human MSCs stimulated proliferation, migration, and differentiation of the endogenous neural stem cells that survived as differentiated neural cells. The results provide a paradigm to explain recent observations in which MSCs or related stem/progenitor cells were found to produce improvements in disease models even though a limited number of the cells engrafted.

Alu Elements↗
PubMed2002

Developmental potentials of hematopoietic and neural stem cells following injection into pre-implantation blastocysts.

Pluripotent embryonic stem (ES) cells are able to differentiate in vivo into all cell types of the fetal and adult organism and in vitro they can differentiate into a variety of cell types. In contrast, multipotent somatic stem cells (SSCs) isolated from fetal and adult tissues differentiate into mature effector cells of their tissue. However, recent studies imply that SSCs can also generate cell types of heterologous tissues indicating unexpected broad differentiation potentials. In order to examine and compare the developmental potentials of SSCs, we exposed hematopoietic stem cells (HSCs) and neural stem cells (NSCs) to an environment that is permissive for the development of all cell types of the embryo, namely the mouse preimplantation blastocyst. Using this approach we were able to detect progeny of HSCs and NSCs frequently in developing chimeric animals. Analysis of 18 different adult tissues revealed minor preferences of HSCs for hematopoietic tissues, while progeny of NSCs were mostly detected in neural tissues. Furthermore we observe that human cord blood-derived CD34+ and CD34+/CD38- HSCs also engraft murine embryos and that human donor contribution persists into adulthood. Our studies show the existence of tissue specific engraftment preferences of HSCs and NSCs and that both stem cell types are non-ES cell-like.

ADP-ribosyl Cyclase↗
PubMed2001

Gene therapy with adenovirus-mediated glial cell line-derived neurotrophic factor and neural stem cells activation after ischemic brain injury.

Recent advancements in molecular biology are made to expect the appearance of the new treatment of stroke patients. One is the administration of neurotrophic factors, and another is the use of neural stem cell. In this report, we performed two experiments. First experiment is administration of glial cell line-derived neurotrophic factor (GDNF) using an adenovirus vector into ischemic rat brain. A replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 min of transient middle cerebral artery occlusion (MCAO) in rats. Infarct volume of the Ad-GDNF injected group at 24 h after the transient MCAO was significantly smaller than that of vehicle or Ad-LacZ treated group. These results suggest that the successful exogenous GDNF gene transfer ameliorates the ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals. Second one is the neural stem cell activation after transient ischemia. 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 dentate gyrus (DG) at 10 and 20 days, and that of BrdU-labeled cells increased in DG at 5 and 10 days after the reperfusion. Immunofluorescence for PSA-NCAM and BrdU showed that a few cells per section were double labeled in DG only at 10 days after the reperfusion. These results suggest different chronological change of PSA-NCAM positive and BrdU-labeled cells in DG after transient ischemia.

Adenoviridae↗
PubMed2003

Neural stem cells.

The adult vertebrate central nervous system (CNS) consists of four major differentiated cell types: neurons, astrocytes, oligodendrocytes and ependymal cells. Historically, there has been a disagreement on how these differentiated cell types are generated in the CNS. Progress remains hindered by the complexity of cell structure in this system, the lack of specific cell surface markers to identify distinct cell types and the presence of numerous transit amplifying cell populations that rapidly generate early progenitors. At present, it is clear that some cells, termed neural stem cells, can generate neurons as well as astrocytes and oligodendrocytes of the glial lineage both in vitro and in vivo. Additionally, specific neural stem cell populations have also exhibited tissue lineage plasticity.

Animals↗
PubMed2004

Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotes production of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells.

Neural stem cells are promising candidates for donor cells in neural transplantation. However, the mechanism by which neural stem cells differentiate into neurons is not well understood. In the present study, a serial analysis of gene expression (SAGE) was carried out to generate a gene file of neural stem (progenitor) cells from the mouse ventral mesencephalon. Among the 15,815 tags investigated, the mRNA of the housekeeping genes (elongation factor 1-alpha, ATPase subunit 6, GAPDH, actin), laminin receptor 1, HSP 70, pleiotrophin, and nestin were highly expressed. Because pleiotrophin (PTN) exhibits mitogenic and trophic effects on neural development and exhibits trophic effects on survival of dopaminergic (DAergic) neurons, we investigated the role of PTN in neurogenesis, especially to DAergic neurons. Here, we show that PTN increased the production of tyrosine hydroxylase (TH)-positive neurons from embryonic stem (ES) cell-derived nestin-positive cells. The expression of Nurr1 mRNA was enhanced by PTN. L-dopa in the culture medium was increased by PTN. This effect was as strong as with sonic hedgehog. Data suggest that PTN mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon, and PTN promotes the production of DAergic neurons from ES cell-derived nestin-positive cells.

Animals↗
PubMed2005

Neural stem cells suppress the hearing threshold shift caused by cochlear ischemia.

Neural stem cells are multipotent progenitor cells that show self-renewal activity. In this study, we assessed the use of neural stem cells for ameliorating ischemia-reperfusion injury of the gerbil cochlea. Neural stem cells were injected into one inner ear through the round window 1 day after ischemic insult. Immunostaining for nestin showed that the distribution of neural stem cells was concentrated within the organ of Corti. Seven days after ischemia, the injury-induced auditory brainstem response threshold shift and progressive inner hair cell damage were markedly less on the neural stem cell-transplanted side. These results suggest that the transplantation of neural stem cells is therapeutically useful for preventing damage to hair cells that occurs after transient ischemia of the cochlea.

Animals↗
PubMed2006

Adult human neural stem cells for autologous cell replacement therapies for neurodegenerative disorders.

Neural stem cells residing in the adult human brain have the potential to provide a source of tissue for self-to-self cell replacement strategies for the treatment of neurodegenerative diseases. Adult human neural stem cells (NSCs) are self renewable in culture and can generate mature neural progeny which display the characteristics of functional neurons and glia. Despite this, a number of concerns remain regarding their current suitability for treating neurodegenerative disorders. It must be demonstrated that desired neuronal types can be generated in clinically significant quantities, and can induce long-lasting functional improvements in well-characterised animal models of neurodegenerative disorders. Furthermore, the risks to patients in terms of tumour formation and side effects must be adequately assessed. Due to the paucity of data on adult human NSCs, a move from preclinical studies to clinical trials in human patients in the foreseeable future is unlikely. If clinical trials with autologous NSCs are pursued as a treatment option for neurodegenerative diseases, then lessons and insights from many years of clinical trials with fetal neural transplantation for Parkinson's and Huntington's diseases will be invaluable, and should be heeded. Issues include experimental versus therapeutic research, standardisation of methodologies, and minimisation of risks and maximisation of benefits.

Adult↗
PubMed2002

When cells become depressed: focus on neural stem cells in novel treatment strategies against depression.

Clinical neuroscience enters a new era in understanding the pathophysiology of depressive illness and the mode of action of antidepressant therapy. While elucidation of factors that lead to depression is still in its infancy, biochemical malfunctions appear to have well defined morphological correlations, especially in the hippocampus. Hippocampus is one of the main sites in the brain habouring neural stem cells. Cytokines and neurotrophic factors like brain-derived neurotrophic factor (BDNF) play a pivotal role in neural plasticity and potentially influence growth and migration of these progenitors. Not surprisingly, antidepressant drugs interfering with neurotransmitters such as serotonin (5-HT) influence neurotrophins like BDNF, since 5-HT homeostasis is essential for brain development, neurogenesis, and neuroplasticity as well as complex behavior. In this review, the new area of neural stem cell research and the avenues of ongoing and future research sustaining the development of novel treatments for depression will be explored.

Animals↗
PubMed1999

Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon.

Multipotent, self-renewing neural stem cells reside in the embryonic mouse telencephalic germinal zone. Using an in vitro neurosphere assay for neural stem cell proliferation, we demonstrate that FGF-responsive neural stem cells are present as early as E8.5 in the anterior neural plate, but EGF-responsive neural stem cells emerge later in development in a temporally and spatially specific manner. By separately blocking EGF and FGF2 signaling, we also show that EGF alone and FGF2 alone can independently elicit neural stem cell proliferation and at relatively high cell densities separate cell nonautonomous effects can substantially enhance the mitogen-induced proliferation. At lower cell densities, neural stem cell proliferation is additive in the presence of EGF and FGF2 combined, revealing two different stem cell populations. However, both FGF-responsive and EGF-responsive neural stem cells retain their self-renewal and multilineage potential, regardless of growth factor conditions. These results support a model in which separate, lineage-related EGF- and FGF-responsive neural stem cells are present in the embryonic telencephalic germinal zone.

Animals↗
PubMed2006

RE1 Silencing transcription factor maintains a repressive chromatin environment in embryonic hippocampal neural stem cells.

The control of gene expression in neural stem cells is key to understanding their developmental and therapeutic potential, yet we know little of the transcriptional mechanisms that underlie their differentiation. Recent evidence has implicated the RE1 silencing transcription factor (REST) in neuronal differentiation. However, the means by which REST regulates transcription in neural stem cells remain unclear. Here, we show that REST recruits distinct corepressor platforms in neural stem cells. REST is able to both silence and repress neuronal genes in embryonic hippocampal neural stem cells by creating a chromatin environment that contains both repressive local epigenetic signature (characterized by low levels of histones H4 and H3K9 acetylation and elevated dimethylation of H3K9) and H3K4 methylation, which are characteristic of gene activation. Furthermore, inhibition of REST function leads to activation of several neuron-specific genes but does not lead to overt formation of mature neurons, supporting the notion that REST regulates part, but not all, of the neuronal differentiation program.

Animals↗
PubMed2004

Using endogenous neural stem cells to enhance recovery from ischemic brain injury.

The use of cell-based therapy may be a valid therapeutic approach to ischemic brain injury. Stem cells have been proposed as a new form of cell based therapy in a variety of disorders, including acute and degenerative brain diseases. Up to date most efforts have concentrated on transplantation of embryonic stem cells (ESC) or neural stem cells (NSCs) obtained from immortalized cell lines into the diseased brain. These procedures require harvesting the appropriate stem cell, expansion in vitro and transplantation. Endogenous NSCs have been identified in the central nervous system where they reside largely in the subventricular zone and in the subgranular zone of the hippocampus. Endogenous NSCs may be capable of self-renewal and differentiation into functional glia and neurons. Manipulation of endogenous NSCs may bypass the need to use ESC as a form of therapy thus avoiding the complex ethical and biological issues involved with ES cells or immortalized cell lines. This review summarizes the evidence recently gathered in support of a therapeutic role for endogenous NSCs in acute experimental stroke.

Animals↗
PubMed2004

[Establishment and characterization of a neural stem cell line (RNSC-FMU 1) from rat brain].

A neural stem cell line (RNSC-FMU 1) from rat brain have been established successfully by isolating and culturing neural stem cells from newborn SD rat brain in vitro with free-serum medium and passaging with mechanical division. The cell line cultured can continuously generate in vitro for long-term and it is 21 months (>100 passages) so far. These cells keep the feature of neural stem cell and normal karyotype. These neural stem cells can be induced to differentiate into neurons, astrocytes and oligodendrocytes. The cells have an extensive self-renewal capacity; its doubling time of proliferation is about 20 h. The cells are also cryopreservable. Tumor formation is not observed in nude mice that explanted with the cells. This cell line is a good tool for research of neural stem cell.

Animals↗
PubMed2005

Bax limits adult neural stem cell persistence through caspase and IP3 receptor activation.

Neural stem cells in the mammalian brain persist and are functional well into adulthood. There is, however, little insight into mechanisms that control adult neural stem cell survival. Mice deficient in the proapoptotic molecule Bax exhibit increased numbers of multipotent progenitor cells in the adult subventricular zone. In vitro, these progenitors behave as neural stem cells and utilize Bax and caspase activation to direct cell death. We demonstrate that the predominate mechanism underlying caspase and Bax-mediated adult neural stem cell death lies in the modulation of calcium flux through interaction with the IP3 receptor.

Animals↗
PubMed2006

her5 expression reveals a pool of neural stem cells in the adult zebrafish midbrain.

Current models of vertebrate adult neural stem cells are largely restricted to the rodent forebrain. To extract the general mechanisms of neural stem cell biology, we sought to identify new adult stem cell populations, in other model systems and/or brain areas. The teleost zebrafish appears to be an ideal system, as cell proliferation in the adult zebrafish brain is found in many more niches than in the mammalian brain. As a starting point towards identifying stem cell populations in this system, we used an embryonic neural stem cell marker, the E(spl) bHLH transcription factor Her5. We demonstrate that her5 expression is not restricted to embryonic neural progenitors, but also defines in the adult zebrafish brain a new proliferation zone at the junction between the mid- and hindbrain. We show that adult her5-expressing cells proliferate slowly, self-renew and express neural stem cell markers. Finally, using in vivo lineage tracing in her5:gfp transgenic animals, we demonstrate that the her5-positive population is multipotent, giving rise in situ to differentiated neurons and glia that populate the basal midbrain. Our findings conclusively identify a new population of adult neural stem cells, as well as their fate and their endogenous environment, in the intact vertebrate brain. This cell population, located outside the forebrain, provides a powerful model to assess the general mechanisms of vertebrate neural stem cell biology. In addition, the first transcription factor characteristic of this cell population, Her5, points to the E(Spl) as a promising family of candidate adult neural stem cell regulators.

Animals↗
PubMed2004

[Isolation culture and identification of human neural stem cells from human embryos].

OBJECTIVE: To obtain and culture the human neural stem cells from the aborted human embryos. METHODS: The neural stem cells were isolated and purified by the specific proliferous culture system of neural stem cells, and the molecular maker and multi-potency of the obtained neural stem cells were identified. RESULTS: Human neural stem cells, which were isolated from 8 - 10 month old aborted human embryos, could express nestin ( a kind of specified antigen of the neural stem cell), and it could be differentiate into neurons and glials. CONCLUSION: Neural stem cells can exist in human embryos, and it can be expanded in vitro.

Cell Differentiation↗
PubMed2004

MHC expression after human neural stem cell transplantation to brain contused rats.

Human neural stem cells survive and improve motor function after transplantation to the contused brain. However, the transplants might be rejected and that depends on the graft immunogenicity, the host immunological status and the immunosuppression strategy. We transplanted human neural stem cells to rats with brain contusion and analyzed the donor and host MHC antigen expression and the effect of a short-term immunosuppression with cyclosporine. In vitro human neural stem cells expressed only MHC-II antigens. This expression was down-regulated 6 weeks after transplantation. The host response was characterized by an increased MHC-II expression which was down-regulated by a longer term of immunosuppression. These findings are novel and necessary in order to understand the immunogenicity of human neural stem cell grafts.

Animals↗
PubMed2001

Transplantation of adult rat hippocampus-derived neural stem cells into retina injured by transient ischemia.

Neural stem cells are capable of differentiating along multiple central nervous system cell-type lineages, and their use as graft material has provided new strategies for the treatment of neuronal damage. We transplanted adult rat hippocampus-derived neural stem cells into eyes of adult rats that underwent ischemia-reperfusion injury. As control, the cells were also injected into normal rats eyes without ischemic insult. The rats were sacrificed at 1, 2, 4, and 8 weeks, and the eyes were examined histochemically. In eyes with the insult, the transplanted cells were well integrated into the host retinas and expressed Map2ab. In the control, none of the cells migrated into the retina. These results suggest that neural stem cells may be used as donor cells for transplantation to repair ischemic-injured retina.

Animals↗