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PubMed2004

Nestin expression is lost in a neural stem cell line through a mechanism involving the proteasome and Notch signalling.

Neural stem cells (NSCs) are believed to repair brain damage primarily through cell replacement: i.e., the ability to regenerate lost neurons and glia in a site-specific fashion. The neural stem cell line, MHP36, has been shown to have this capacity, but we have little idea of the molecular mechanisms that control the differentiation of such cells during brain repair. In this study we show that an early event in the differentiation of MHP36 cells, both in vivo and in vitro, is the loss of expression of the intermediate filament protein, nestin. We use a co-culture assay to show that loss of nestin is fast, being detectable after just 1 h and complete in 4 h, and is controlled by proteasome degradation rather than down-regulation of de novo nestin synthesis. We also show that nestin loss is regulated by Notch, and mediated by cell contact.

Acetylcysteine↗
PubMed2003

Neural stem cells as delivery vehicles.

The discovery of neural stem cells (NSCs) has changed our long-held view that the adult mammalian central nervous system (CNS) is postmitotic and lacks the capability for self-repair. The role of NSCs in physiological and pathological processes in the brain is slowly emerging. We are now able to isolate, expand, genetically engineer and transplant NSCs. An important characteristic of NSCs, not fully understood so far, is their migratory ability and their tropism to brain pathology. The migratory ability of NSCs and their capacity to differentiate into all neural phenotypes gives us a potentially powerful tool for the treatment of both diffuse and localised neurologic disorders. The delivery of gene products by NSCs to specific sites in the CNS can maximise the efficiency of delivery and minimise the unwanted exposure of surrounding intact tissue. Here, the recent preclinical advances in the use of NSCs for the delivery of therapeutic products are reviewed, in particular the employment of their migratory potential and the homing ability to pathology in the nervous system.

Animals↗
PubMed1996

Host regulation of glial markers in intrastriatal grafts of conditionally immortalized neural stem cell lines.

After transplantation into the adult CNS the immortalized neural stem cell lines ST14A and HiB5 differentiate preferentially into glia-like cells. After lesions of the host brain, which activate resting glial populations, the grafted cells responded with up-regulation of glial markers and a change in morphology towards a reactive state. The protein expression followed the same pattern as in the host glial population. The results show that the astrocytes formed by the grafted neural stem cells become functionally integrated in the host brain and that they may take an active part in the reactive gliosis caused by brain damage.

Analysis of Variance↗
PubMed2005

Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome.

Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.

Analysis of Variance↗
PubMed2002

Amphiregulin is a mitogen for adult neural stem cells.

Neurons are continuously generated from stem cells in the hippocampus and along the lateral ventricles in the adult brain. Neural stem cells can be propagated in vitro in the presence of epidermal growth factor (EGF) or fibroblast growth factor-2. We report here that amphiregulin, a growth factor related to EGF, is a mitogen for adult mouse neural stem cells in vitro and displays potency similar to that of EGF. Neural stem cell cultures can be initiated and the cells propagated as efficiently in the presence of amphiregulin only as with EGF. Furthermore, we show that amphiregulin is expressed in the choroid plexus of the ventricular system and in the hippocampus in the adult brain, suggesting that amphiregulin may participate in the regulation of neural stem cell proliferation and neurogenesis in the adult brain.

Age Factors↗
PubMed2004

[Labeling neural stem cells with superparamagnetic iron oxide in vitro and tracking after implantation with MRI in vivo].

OBJECTIVE: To evaluate the feasibility of monitoring the neural stem cells implanted into the brain by the technique of labeling with superparamagnetic iron oxide (SPIO). METHODS: Neural stem cells were isolated from the cerebral cortex of newborn Wister rats and cultured. SPIO particles and poly-L-lysine were added into the medium to be co-cultured foe one hour. After the formation of neurospheres, Prussian blue staining was conducted and transmission electron microscopy was used to identify the iron particles in these neural stem cells. Sixteen adult female Wistar rats underwent transplantation of labeled neural stem cells into the right side of brain and non-labeled cells were transplanted into the contralateral part as controls. 1, 2, 4, 6, and 7 weeks after the transplantation, MRI examination with the scanning sequences of SE T2WI, FSE T2WI, and GRE T2 * respectively was conducted on the brains of the rats. Four rats at each time point were killed and their brains were taken out to undergo HE staining and Prussian blue staining to track the presence of labeled-cells. RESULTS: After the addition of SPIO the neurospheres continued to proliferate and differentiate normally. Electron microscopy showed vacuolar structures of different sizes under the cytoplasma membrane within and outside which there were high-density iron particles. Prussian blue staining showed numerous blue stained particles in the cytoplasm of the labeled cells. Remarkable low signal change was seen in the right brain transplanted with labeled cells, especially in the condition of scanning sequence of GRET2. Such change could be seen up to 7 weeks after the transplantation. No signal change was found in the left brain. CONCLUSION: SPIO labeling technique is useful in monitoring the outcome of transplanted neural stem cells.

Animals↗
PubMed2005

Adult neural stem cell therapy: expansion in vitro, tracking in vivo and clinical transplantation.

Neural stem cells (NSCs) are present not only in the developing nervous systems, but also in the adult human central nervous system (CNS). It is long thought that the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus are the main sources of human adult NSCs, which are considered to be a reservoir of new neural cells. Recently adult NSCs with potential neural capacity have been isolated from white matter and inferior prefrontal subcortex in the human brain. Rapid advances in the stem cell biology have raised appealing possibilities of replacing damaged or lost neural cells by transplantation of in vitro-expanded stem cells and/or their neuronal progeny. However, sources of stem cells, large scale expansion, control of the differentiations, and tracking in vivo represent formidable challenges. In this paper we review the characteristics of the adult human NSCs, their potentiality in terms of proliferation and differentiation capabilities, as well as their large scale expansion for clinical needs. This review focuses on the major advances in brain stem cell-based therapy from the clinical perspective, and summarizes our work in clinical phase I-II trials with autologuous transplantation of adult NSCs for patients with open brain trauma. It also describes multiple approaches to monitor adult human NSCs labeled superparamagnetic nanoparticles after transplantation and explores the intriguing possibility of stem cell transplantation.

Animals↗
PubMed2004

Subventricular zone neural stem cells remodel the brain following traumatic injury in adult mice.

Neural stem cells have recently been shown to contribute to the cellular remodeling that occurs following traumatic brain injury (TBI). Potential sources for these stem cells from within the brain include the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus. Using intraventricular injections of the fluorescent vital dye DiO in mice, we demonstrate that the subventricular zone population of stem cells can be reliably labeled and followed over time. By following these injections with a contralateral controlled cortical injury we demonstrate that cells from the subventricular zone migrate to the most proximally injured cortical areas. Using doublelabeling immunohistochemistry with anti-nestin, anti-GFAP, and anti-NeuN antibodies we demonstrate that labeled cells from the subventricular zone contribute primarily to the astroglial scar following injury. We do not observe any contribution to deeper areas of injury including the hippocampus. These data demonstrate that the subventricular zone contributes to brain remodeling following TBI, though neural stem cell sources outside the subventricular zone appear to play reparative roles as well.

Animals↗
PubMed1996

Is there a neural stem cell in the mammalian forebrain?

Neural precursor cells have been of interest historically as the building blocks of the embryonic CNS and, most recently, as substrates for restorative neurological approaches. The majority of previous in vitro studies of the regulation of neural-cell proliferation by polypeptide growth factors, and in vivo studies of neural lineage, argue for the presence of precursors with limited proliferative or lineage potential in the mammalian CNS. This is in contrast to renewable tissues, such as the blood or immune system, skin epithelium and epithelium of the small intestinal crypts, which contain specialized, self-renewing cells known as stem cells. However, recent in vitro and in vivo studies from our and other laboratories lead us to conclude that neural stem cells, with self-renewal and multilineage potential, are present in the embryonic through to adult mammalian forebrain.

Animals↗
PubMed2004

Requirement for neurogenesis to proceed through the division of neuronal progenitors following differentiation of epidermal growth factor and fibroblast growth factor-2-responsive human neural stem cells.

Epidermal growth factor (EGF)- and fibroblast growth factor-2 (FGF-2)-responsive human neural stem cells may provide insight into mechanisms of neural development and have applications in cell-based therapeutics for neurological disease. However, their biology after expansion in vitro is currently poorly understood. Cells grown in either EGF or FGF-2 or a combination of both mitogens displayed characteristically similar levels of transcriptional activation and comparable proliferative profiles with linear cell-cycle kinetics and possessed similar neuronal differentiation capabilities. These data support the view that human neurospheres at later stages of expansion (>10 weeks) are comprised overwhelmingly of a single type of stem cell responsive to both EGF and FGF-2. After mitogen withdrawal and neurosphere plating, bromodeoxyuridine pulse-chase experiments revealed that the stem cells did not undergo differentiation directly into neurons. Instead, most immature neurons arose via the division of emerging progenitor cells in the absence of exogenous EGF or FGF-2. Neurogenesis was abolished by application of high concentrations of either EGF/FGF-2 or the mitotic inhibitor cytosine-b-arabinofuranoside, suggesting that there is an obligatory requirement for at least one round of cell division in the absence of mitogens as a prelude to terminal neuronal differentiation. The differentiation of human neurospheres provides a useful model of human neurogenesis, and the data presented indicate that it proceeds through the division of committed neuronal progenitor cells rather than directly from the neural stem cell.

Antineoplastic Agents↗
PubMed2003

Biology and clinical application of neural stem cells.

Neural stem cells, which exist in various regions of the CNS throughout the mammalian lifespan, can be expanded and induced to differentiate into neurons and glia in vitro and in vivo. Because of these characteristics, there has been increasing interest in the identification and characterization of neural stem cells and neural progenitor cells both for basic developmental biology studies and for therapeutic applications to the damaged brain. Transplantation of neural stem cells or their derivatives into a host brain and the proliferation and differentiation of endogenous stem cells by pharmacological manipulations are potential treatments for many neurodegenerative diseases and brain injuries, such as Parkinson's disease, brain ischemia and spinal cord injury. Continued progress in neural stem cell research is providing a new future for brain repair.

Animals↗
PubMed2005

Beta1 integrins and neural stem cells: making sense of the extracellular environment.

Neural Stem Cells (NSC) are present in the developing and adult CNS. In both the embryonic and adult neurogenic regions, beta1 integrins may act as sensors for the changing extracellular matrix. Here we highlight the integrative functions that beta1 integrins may play in the "niche" by regulating NSC growth factor responsiveness in a timely and spatially controlled manner. beta1 integrins may provide NSC with the capacity to react to a dynamic "niche", and to respond adequately by either remaining as stem cells or by differentiating and migrating away to shape the developing cortex.

Animals↗
PubMed2006

Cultured rat astrocytes give rise to neural stem cells.

Previously, we reported the occurrence of neural stem cells (NSCs) around an area of damage after rat traumatic brain injury (TBI), but it was unclear if this was due to blastgenesis in astrocytes, or to NSCs migrating from the subventricular zone (SVZ). In this study, NSCs were isolated and cultured from cultured type 1 astrocytes taken from newborn rat cortex in which the subventricular zone and hippocampus had been discarded. All cultured type 1 astrocytes showed glial fibrillary acidic protein (GFAP) immunopositivity. Nestin immunopositive spheres were isolated from type 1 astrocytes and cultured in the presence of bFGF and EGF in the medium. Neurospheres differentiated into Tuj1-, GFAP- and A2B5-positive cells after 4 days of culture without bFGF and EGF. These results indicate that isolated neurospheres from brain cortex astrocytes can differentiate into neurons and glia and might contribute to neurogenesis and neuroplasticity.

Animals↗
PubMed2005

Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes.

Differentiation induction of neural stem cells (NSCs) into oligodendrocytes during embryogenesis is the result of a complex interaction between local induction factors and intracellular transcription factors. At the early stage of differentiation, in particular, the helix-loop-helix transcription factors Olig1 and Olig2 have been shown to be essential for oligodendrocyte lineage determination. In view of the possible application of NSCs as a source for remyelinating cell transplants in demyelinating diseases (e.g., multiple sclerosis), in vitro procedures need to be developed to drive the oligodendrocyte differentiation process. Mere culture in medium supplemented with major embryonic oligodendrogenic induction factors, such as Sonic hedgehog, results in oligodendrocyte differentiation of only about 10% of NSCs. We previously showed that induction of Olig1 expression by gene transfection could indeed initiate the first stage of oligodendrocyte differentiation in NSCs, but appeared to be unable to generate fully mature, functional oligodendrocytes. In this study, we transfected NSCs isolated from the embryonic mouse brain with the Olig2 gene and found that the introduced overexpression of Olig2 could induce the development of fully mature oligodendrocytes expressing the transcription factor Nkx2.2 and all major myelin-specific proteins. Moreover, Olig2-transfected NSCs, in contrast to nontransfected NSCs, developed into actively remyelinating oligodendrocytes after transplantation into the corpus callo-sum of long-term cuprizonefed mice, an animal model for demyelination. Our results show that transfection of genes encoding for oligodendrogenic transcription factors can be an efficient way to induce the differentiation of NSCs into functional oligodendrocytes.

Animals↗
PubMed2002

The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma.

Neural stem cells (NSCs) are capable of tracking migrating glioma cells. To exploit this tropism to generate an antitumor T-cell response, particularly against disseminating tumor pockets, we inoculated intracranial glioma-bearing mice with interleukin 12 (IL-12) producing NSCs. Intratumoral therapy with IL-12-secreting NSCs prolonged survival compared to treatment with nonsecretory NSCs or saline. NSCs demonstrated strong tropism for disseminating glioma, and IL-12-secreting NSC therapy was associated with enhanced T-cell infiltration in tumor microsatellites and long-term antitumor immunity. These results indicate that the use of tumor tracking NSCs represents a potent new therapeutic modality for glioma.

3T3 Cells↗
PubMed2004

Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.

The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.

Adult↗
PubMed2004

In vitro culture and induced differentiation of adult rat neural stem cells from the corpus striatum.

OBJECTIVE: To investigate the in vitro multipotential differentiation of neural stem cells from adult rat corpus striatum. METHODS: The neural stem cells isolated from adult rat corpus striatum were cultured in serum-free medium to obtain cell suspension before monoclonal subculturing and differential induction. Immunocytochemical staining and reverse transcriptional PCR (RT-PCR) were performed to identify the properties of the differentiated cells. RESULTS: Numerous cell clusters were formed in the phase of monoclonal culture, and different types of cells were observed 3 d after induction with fetal bovine serum. The differentiated cells contained cells positive for nestin, neuron-specific enolase (NSE) positive cells, and glial fibrillary acidic protein (GFAP) positive cells. RT-PCR identified expressions of the transcripts for neural cell-associated genes including brain factor-1, gamma-aminobutyric acid alpha-receptor gamma-subunit, tyrosine hydroxylase and tryptophan hydroxylase. CONCLUSION: The cells separated from adult rat corpus striatum possess the ability of self-proliferation and multipotential differentiation, and are identified as the stem cells of the central nervous system.

Animals↗
PubMed2004

Expression and function of orphan nuclear receptor TLX in adult neural stem cells.

The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.

Aging↗