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

Keyoung, H. Michael; Roy, Neeta S.; Benraiss, Abdellatif; Louissaint, Abner; Suzuki, Akira; Hashimoto, Mitsuhiro; Rashbaum, William K.; Okano, Hideyuki; Goldman, Steven A.

doi:10.1038/nbt0901-843

Cited by 169 publications

(137 citation statements)

References 45 publications

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“…The potential advantages in NSCs are as nontransformed cells that are able to self-renew indefinitely, allowing their expansion in large quantities. As discussed, mammalian multi-potential NSCs support neurogenesis and gliogenesis within specific areas of the CNS during development and adulthood, and can be isolated from fetal and adult brains [10,132,133]. The notion that glial committed neural stem cells may combine the capacity for self-renewal and plasticity of stem cells, together with the remyelinating properties of OPCs, led to identification of such precursors in the developing brain [134].…”

Section: Cell Replacementmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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Section: Cell Replacementmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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“…Thus, an enriched cell preparation containing only desired and lineage-restricted phenotypes may greatly reduce graft immunogenicity, while improving the likely functional outcome of transplantation [34]. For instance, neural and glial progenitors isolated on the basis of their expression of defined stem and progenitor cell markers, such as the intermediate filament nestin, the RNA binding protein Musashi, the transcription factor Sox2, or the glial progenitor marker A2B5, have all been shown to stably engraft for long periods of time in xenografted mice and rats, with minimal immunosuppression [35][36][37][38][39]. Future studies of striatal neuronal engraftment may profitably study the effect of pre-transplant phenotypic enrichment, as a means of mitigating rejection potential, and of thereby increasing graft acceptance and functional integration.…”

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confidence: 99%

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Benraiss

Goldman

2011

Neurotherapeutics

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“…5 With this neural stem/progenitor cell-specific expression, nestin has been utilized to harvest neuronal progenitor cells from embryonal stem cells. 6 Furthermore, significant levels of nestin have been detected in human gliomas. 7,8 Recently, we re-evaluated the nestin expression in 71 cases of brain tumors including 40 cases of gliomas that ranged from low to high malignancy grades.…”

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confidence: 99%

Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene

Aihara

Sugawara

Torii

et al. 2004

Laboratory Investigation

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Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5 0 upstream promoter (5 0 UP) gave the highest activity, followed by 5 0 UP, and the second intron plus 5 0 UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.

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

Cited by 169 publications

References 45 publications

Cell Therapy for Multiple Sclerosis

Cell Therapy for Multiple Sclerosis

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene

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