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PubMed2000

Cell cycle regulators in neural stem cells and postmitotic neurons.

In the mammalian central nervous system, neurons withdraw from the cell cycle immediately after their differentiation from proliferative neuroepithelial cells. Even while postmitotic neurons remain in permanent mitotic quiescence, they express a number of cell cycle regulators required for cell cycle progression. This review focuses on the expression and functions of members of the retinoblastoma protein (Rb) family (Rb, p107, p130) and necdin, all of which are growth suppressors that interact with the viral oncoproteins and the E2F family proteins. These molecules are differentially expressed in proliferative neural progenitors and postmitotic neurons in the developing neuroepithelium in vivo and differentiating embryonal carcinoma cells in vitro. During neurogenesis, dysfunction of the Rb family proteins causes impaired neuronal differentiation accompanied by cell death (apoptosis). Thus, the Rb family proteins are essential for both terminal mitosis of neuronal progenitors and survival of nascent neurons. However, the Rb family proteins seem to be dispensable for the maintenance of the postmitotic state of terminally differentiated neurons. Necdin is expressed exclusively in postmitotic cells and may contribute to their permanent mitotic arrest. These cell cycle regulators coordinately act in the generation, survival and demise of postmitotic neurons.

Animals↗
PubMed2006

[Isolation and culture of neural stem cell from rat olfactory epithelium].

OBJECTIVE: To isolate and culture neural stem cell (NSC) from rat olfactory epithelium and investigate the characteristics of its proliferation and differentiation. METHOD: NSC from postnatal three-day (P3) and zinc sulfate in situ injured adult rat olfactory epithelium was cultured with DMEM/F12 (1 : 1) containing 10% heat-inactivated fetal bovine serum. NSC and specific neural cells differentiated from NSC were identified with indirect immunofluorescence. Growth curve of NSC from P3 and adult rat and the effect of growth factors were measured using MTT method. RESULT: Neurosphere-forming cells were isolated and collected with diluted purification method from P3 and adult rat olfactory epithelium. These neurosphere-forming cells were nestin immuno-positive and cytokeratin immuno-negative, and could differentiated into neuronal specific enolase (NSE) immuno-positive neurons and glial fibrillary acidic protein (GFAP) immuno-positive astrocytes when transferred in MEM. The viability of NSC had no significant difference between P3 and adult rat (P > 0.05). The forming rate of neurosphere of P3 and adult rat olfactory epithelium was 0.05% - 0.10%. Fibroblast growth factor-basic could significantly promote the proliferation of NSC from epithelium, while epidermal growth factor showed no effect on the proliferation of the NSC. CONCLUSION: NSC with self-renewal capacity and multipotential differentiation can be isolated and cultured from P3 and adult rat olfactory epithelium.

Animals↗
PubMed2004

Wnt proteins promote neuronal differentiation in neural stem cell culture.

Wnt signaling is implicated in the control of cell growth and differentiation during CNS development from studies of mouse and chick models, but its action at the cellular level has been poorly understand. In this study, we examine the in vitro function of Wnt signaling in embryonic neural stem cells, dissociated from neurospheres derived from E11.5 mouse telencephalon. Conditioned media containing active Wnt-3a proteins are added to the neural stem cells and its effect on regeneration of neurospheres and differentiation into neuronal and glial cells was examined. Wnt-3a proteins inhibit regeneration of neurospheres, but promote differentiation into MAP2-positive neuronal cells. Wnt-3a proteins also increase the number of GFAP-positive astrocytes but suppress the number of oligodendroglial lineage cells expressing PDGFR or O4. These results indicate that Wnt-3a signaling can inhibit the maintenance of neural stem cells, but rather promote the differentiation of neural stem cells into several cell lineages.

Animals↗
PubMed2005

Characteristics of human neural stem cells in vitro and after transplantation into rat brain.

We studied the effect of culturing conditions on the fate of human neural stem cells after transplantation into rat brain. Human neural stem cells cultured in the presence of mitogens without LIF migrated along the ependyma and cerebral vessels of recipients, but to a great extent degenerated by the 20th day after transplantation. Neural stem cells cultured with LIF migrated, apart from the above mentioned pathways, in the cortex and hippocampus, well survived; proliferating cells were retained 30 days after transplantation.

Animals↗
PubMed1999

Amino-terminal region of secreted form of amyloid precursor protein stimulates proliferation of neural stem cells.

Beta-amyloid precursor protein (APP) has been reported to be expressed in the CNS from the early stages of development. However, the functional role of APP during early development remains unclear. In the present study, we found that the secreted form of APP (sAPP) significantly enhanced proliferation of neural stem cells. Cells were prepared from 13-day embryonic rat neocortex, which was dissected with a Pasteur pipette to make cell clusters. After 12 h of cultivation in the medium without serum, cells around the centre of the cluster were still nestin-positive proliferative cells, i.e. neural stem cells. To determine whether the proliferation of cells was regulated by sAPP, cultures were treated with recombinant sAPP695, the secreted form of human APP695 produced by yeast. Both DNA synthesis and expression of proliferating cell nuclear antigen markedly increased after 5 h of sAPP695 addition. The enhancement of DNA synthesis by sAPP695 stimulation was blocked by the 22C11 monoclonal antibody specific for the amino-terminal region of sAPP. Then, we examined the effect of the amino-terminal fragment of sAPP and the epitope peptide of 22C11 antibody, and found that both of them also promoted DNA synthesis, suggesting that the amino-terminal region of sAPP is responsible for the biological activity. Our findings indicate the possibility that sAPP enhances proliferation of neural stem cells in vivo and plays an important role during the early CNS development.

Amyloid beta-Protein Precursor↗
PubMed2005

Pituitary adenylate cyclase-activating polypeptide promotes differentiation of mouse neural stem cells into astrocytes.

We have found that pituitary adenylate cyclase-activating polypeptide (PACAP) employed at the physiological concentrations induces the differentiation of mouse neural stem cells into astrocytes. The differentiation process was not affected by cAMP analogues such as dibutylic cAMP (db-cAMP) or 8Br-cAMP or by the specific competitive inhibitor of protein kinase A, Rp-adenosine-3',5'-cyclic monophosphothioate triethylamine salt (Rp-cAMP). Expression of the PACAP receptor (PAC1) in neural stem cells was detected by both RT-PCR and immunoblot using an affinity-purified antibody. The PACAP selective antagonist, PACAP(6-38), had an inhibitory effect on the PACAP-induced differentiation of neural stem cells into astrocytes. These results indicate that PACAP acts on the PAC1 receptor on the plasma membrane of mouse neural stem cells, with the signal then transmitted intracellularly via a PAC1-coupled G protein, does not involve Gs. This signaling mechanism may thus play a crucial role in the differentiation of neural stem cells into astrocytes.

Animals↗
PubMed2004

Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor.

Hypoxia as well as global and focal ischemia are strong activators of neurogenesis in the adult mammalian central nervous system. Here we show that the hypoxia-inducible vascular endothelial growth factor (VEGF) and its receptor VEGFR-2/Flk-1 are expressed in clonally-derived adult rat neural stem cells in vitro. VEGF stimulated the expansion of neural stem cells whereas blockade of VEGFR-2/Flk-1-kinase activity reduced neural stem cell expansion. VEGF was also infused into the lateral ventricle to study changes in neurogenesis in the ventricle wall, olfactory bulb and hippocampus. Using a low dose (2.4 ng/d) to avoid endothelial proliferation and changes in vascular permeability, VEGF stimulated adult neurogenesis in vivo. After VEGF infusion, we observed reduced apoptosis but unaltered proliferation suggesting a survival promoting effect of VEGF in neural progenitor cells. Strong expression of VEGFR-2/Flk-1 was detected in the ventricle wall adjacent to the choroid plexus, a site of significant VEGF production, which suggests a paracrine function of endogenous VEGF on neural stem cells in vivo. We propose that VEGF acts as a trophic factor for neural stem cells in vitro and for sustained neurogenesis in the adult nervous system. These findings may have implications for the pathogenesis and therapy of neurodegenerative diseases.

Animals↗
PubMed2004

Neural stem cells and the quest for restorative neurology.

A great deal of interest has attracted the attention of researchers on the potential use of (neural) stem cells in cell replacement or restorative therapies for heretofore incurable CNS pathologies such as brain stroke, spinal cord injury, Parkinson's disease or multiple sclerosis. This short perspective illustrates our view of neural stem cell research with a focus on the stem cell concept, on the in situ identity of neural stem cells and on selected aspects of embryonic and adult neurogenesis. A brief survey of current stem cell-based experimental literature tries to provide a realistic picture of how far we have gone in the quest to establish a restorative neurology.

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PubMedDate not supplied

Neural stem cells in aging and disease.

Aging in the central nervous system is associated with progressive loss of function which is exacerbated by neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The two primary cell replacement strategies involve transplantation of exogenous tissue, and activation of proliferation of endogenous cells. Transplanted tissue is used to either directly replace lost tissue, or to implant genetically engineered cells that secrete factors which promote survival and/or proliferation. However, successful application of any cell replacement therapy requires knowledge of the complex relationships between neural stem cells and the more restricted neural and glial progenitor cells. This review focuses on recent advances in the field of stem cell biology of the central nervous system, with an emphasis on cellular and molecular approaches to replacing cells lost in neurodegenerative disorders.

Aging↗
PubMed1999

Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo.

Stem cells are found in various organs where they participate in tissue homeostasis by replacing differentiated cells lost to physiological turnover or injury. An investigation was performed to determine whether stem cells are restricted to produce specific cell types, namely, those from the tissue in which they reside. After transplantation into irradiated hosts, genetically labeled neural stem cells were found to produce a variety of blood cell types including myeloid and lymphoid cells as well as early hematopoietic cells. Thus, neural stem cells appear to have a wider differentiation potential than previously thought.

Animals↗
PubMed2001

The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells.

The cytokines that signal through the common receptor subunit gp130, including ciliary neurotrophic factor (CNTF), interleukin-6, leukemia inhibitory factor (LIF) and oncostatin M, have pleiotropic functions in CNS development. Given the restricted expression domain of the CNTF receptor alpha (CNTFR) in the developing forebrain germinal zone and adult forebrain periventricular area, we have examined the putative role of CNTFR/LIFR/gp130-mediated signaling in regulating forebrain neural stem cell fate in vivo and in vitro. Analysis of LIFR-deficient mice revealed that a decreased level of LIFR expression results in a reduction in the number of adult neural stem cells. In adult LIFR heterozygote (+/-) mice, the number of neural stem cells and their progeny in the forebrain subependyma and TH-immunoreactive neurons in the olfactory bulb were significantly reduced. Intraventricular infusion of CNTF into the adult mouse forebrain, in the absence or presence of epidermal growth factor (EGF), enhanced self-renewal of neural stem cells in vivo. Analyses of EGF-responsive neural stem cells proliferating in vitro found that CNTF inhibits lineage restriction of neural stem cells to glial progenitors, which in turn results in enhanced expansion of stem cell number. These results suggest that CNTFR/LIFR/gp130-mediated signaling supports the maintenance of forebrain neural stem cells, likely by suppressing restriction to a glial progenitor cell fate.

Animals↗
PubMedDate not supplied

[Behavior and differentiation of the neural stem cells in vivo].

We studied the behavior and differentiation of human and rat neural stem cells after transplantation in the adult rat brain without immunosuppression. The rat stem cells were isolated from the presumptive neocortex of 15-day-old embryos. The human cells were isolated from the ventricular brain zone of 9-week-old embryos and cultivated for two weeks before transplantation. The results of histomorphological studies suggest that the microenvironment factors did not suppress the growth or development of transplanted stem cells. Both rat and human embryonic multipotent neural cells showed similar behavior and differentiation into neurons and glial cells. After transplantation, they continued to mitotically divide and migrated from the graft area to the surrounding tissue of a recipient brain. The presumptive glial cells migrated preferentially along the capillaries and fibrous structures of the recipient brain. Similar behavior of the rat and human neural stem cells in the microenvironment of the recipient adult rat brain and the absence of immune reaction suggest that the transplantation into the rat brain may serve as a model for studying the developmental biology of the human stem cells.

Animals↗
PubMed2002

Flow cytometric analysis of neural stem cells in the developing and adult mouse brain.

Despite recent progress in the neural stem cell biology, their cellular characteristics have not been described well. We investigated various characteristics of neural stem cells (NSCs) in vivo during CNS development, using FACS to identify the NSCs. We first examined stage-dependent changes in the physical parameters, using forward scatter (FSC) and side scatter (SSC) profiles, of NSCs from the developing striatum, where they appear to be active throughout the life of mammals. NSCs were divided into several fractions according to their FSC/SSC profile. With development, their number decreased in the FSC(high) fractions but increased in the FSC(low)/SSC(high) fraction, whereas NSCs were significantly concentrated in the fraction containing the largest cells (about 20 microm in diameter) at any stage, which were mostly the cells with the highest nestin-enhancer activity. Furthermore, we demonstrated that, at all stages examined, the "side population" (SP), defined as the Hoechst 33342 low/negative fraction, which is known to be a stem cell-enriched population in bone marrow, was also enriched for Notch1-positive immature neural cells (about 60%) from the developing striatum. However, these immature SP cells were not detected in the large-cell fraction, however, but were concentrated instead in the FSC(low/mid) fractions. FACS analysis showed that SP cells from adults were included to some extent in the CD24(low)/PNA(low) fraction, where NSCs were greatly concentrated. Collectively, the characteristics of NSCs were not uniform and changed developmentally.

Age Factors↗
PubMed2004

Implantation of neural stem cells via cerebrospinal fluid into the injured root.

In avulsion injury of the dorsal root, regenerating axons cannot extend through the entry zone, i.e. the transition zone between peripheral and central nervous systems, due to the discontinuity between Schwann cells and astrocytes. We infused neural stem cells through the 4th ventricle in an attempt to enhance axonal growth in injured dorsal roots. Infused stem cells were attached to, and integrated into, the lesion of the root and became associated with axons in the same manner as Schwann cells or perineurial sheath cells in the peripheral nerve, and as astrocytes in the central nerve area. These findings suggest that neural stem cells integrated by infusion through CSF might have a beneficial effect on nerve regeneration by inducing a continuity of Schwann cells and astrocytes at the transition zone.

Animals↗
PubMed2006

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.

Adult Stem Cells↗
PubMed2006

De novo and salvage pathways of DNA synthesis in primary cultured neurall stem cells.

We studied the de novo and salvage pathways of DNA synthesis in sphere-forming neural stem cells obtained from mouse embryos by a neurosphere method. The former pathway needs folic acid (FA) for nucleotide biosynthesis, while the latter requires deoxyribonucleosides (dNS). We examined the proliferative activity of sphere-forming cells in E14.5 embryos by counting the number of spheres formed in media that lacked FA and/or dNS. Proliferation failure and apoptosis occurred in a deficient medium lacking of both FA and dNS. Spheres formed in the deficient medium supplemented with dNS, without FA, did not produce neuron, but rather only seem to generate astrocytes and oligodendrocytes when plated under differentiation condition in culture. On the other hand, a subpopulation of cultured cells formed spheres in the deficient medium supplemented with FA alone in an appropriate concentration, and did possess the self-renewing and multipotential characteristics of neural stem cells. Spheres formed in the media containing low dose Azathioprine and methotrexate, inhibitors of de novo DNA synthesis, were selectively prevented from producing neurons even in the presence of FA. These results suggested that activating de novo DNA synthesis was needed for neural stem cells to proliferate with multipotentiality.

Age Factors↗
PubMed2005

Reduction of neural and vascular damage by transplantation of VEGF-secreting neural stem cells after cerebral ischemia.

We determined the role of VEGF-transfected neural stem cells (NSCs) transplantation in rat brain subjected to ischemia. Fetal NSCs were cultured from E14 days SD rats and transfected with VEGF121 gene by using lipofectamine technique. Temporary middle cerebral artery occlusion (tMCAO) models were established and randomly divided into 1: control group, 2: PBS transplantation group, 3: NSCs transplantation group and 4: VEGF-secreting NSCs transplantation group. Grafts were transplanted into the penumbra zones 3 days after tMCAO model established. Neurological Severity Score (NSS) was checked in all groups 2-12 weeks after transplantation. By using immunofluorescent staining, VEGF expression of transplanted cells, differentiation and migration of transplanted NSCs after transplantation were detected. VEGF gene-transfected neural stem cells expressed gene products during the first 2 weeks. NSS in this group was significantly lower compared with that in other 3 groups 12 weeks after transplantation. VEGF gene-transfected NSCs migrated and expressed VEGF in hosts' brains, some of them differentiated to neurons 12 weeks after transplantation. VEGF-transfected NSCs expressed gene products during the early time after transplantation, which reduce brain injury through protecting the vascular system against ischemic attack.

Animals↗
PubMed2006

The gene expression profile of PDGF-treated neural stem cells corresponds to partially differentiated neurons and glia.

We have previously shown that platelet-derived growth factor AA (PDGF-AA) stimulates the expansion of neuronal progenitors from neural stem cells, but is unable to replace fibroblast-growth factor 2 (FGF-2) as a stem cell mitogen. In the present study, we compared gene expression in neural stem cells that were grown in the presence of FGF-2 and in cells cultured with PDGF-AA or in the absence of growth factor, which induces differentiation. The genetic program elicited by PDGF-AA (156 significantly regulated genes) was not unique, but an intermediate between the ones of FGF-2-cultured stem cells and differentiated cells. These observations are compatible with the hypothesis that PDGF-AA induces a partial differentiation of neural stem cells, which retain the ability to proliferate, rather than acting solely as an instructing agent for neuronal differentiation. Finally, the transcriptional signature of stem cells grown with FGF-2 included a large number of genes over-expressed in gliomas and a core set of conserved genes periodically expressed during the eukaryote cell cycle.

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