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      Comparative analysis of human embryonic stem cell-derived neural stem cells as an in vitro human model

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          Abstract

          Alternative cell models of human neural stem cells (hNSCs) have been developed and used for investigations ranging from in vitro experiments to in vivo clinical studies. However, a cell model capable of mimicking the ʻnormalʼ state of hNSCs is mandatory in order to extrapolate the results of these studies to humans. In the present study, to select a more suitable hNSC model for developing human-based experimental platforms, two representative hNSC types were compared, namely human embryonic stem cell (hESC)-derived hNSCs and ReNcell CX cells, which are well-characterized immortalized hNSC lines. The hNSCs, differentiated from hESCs via human neuroectodermal sphere (hNES) formation, recapitulated the molecular and cellular phenotypes of hNSCs, including NSC marker expression and terminal neuronal differentiation potential. Comparative analyses of the transcriptome profiles of the hESC-derived hNESs and ReNcell CX hNSCs showed that the differentiated hNESs were analogous to the ReNcell CX cells, as demonstrated by principal component analysis and hierarchical sample clustering. The hNSC-specific transcriptome was presented, comprising commonly expressed transcripts between hNESs derived from hESCs and ReNcell CX cells. To elucidate the molecular mechanisms associated with the hNSC identity, the hNSC-specific transcriptome was analyzed using pathway and functional annotation clustering analyses. The results suggested that hESC-derived hNESs, an expandable and accessible cell source, may be used as a relevant hNSC model in a wide range of neurological investigations.

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          Promotion of direct reprogramming by transformation-deficient Myc.

          Induced pluripotent stem cells (iPSCs) are generated from mouse and human fibroblasts by the introduction of three transcription factors: Oct3/4, Sox2, and Klf4. The proto-oncogene product c-Myc markedly promotes iPSC generation, but also increases tumor formation in iPSC-derived chimeric mice. We report that the promotion of iPSC generation by Myc is independent of its transformation property. We found that another Myc family member, L-Myc, as well as c-Myc mutants (W136E and dN2), all of which have little transformation activity, promoted human iPSC generation more efficiently and specifically compared with WT c-Myc. In mice, L-Myc promoted germline transmission, but not tumor formation, in the iPSC-derived chimeric mice. These data demonstrate that different functional moieties of the Myc proto-oncogene products are involved in the transformation and promotion of directed reprogramming.
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            Neural stem cells: historical perspective and future prospects.

            How a single fertilized cell generates diverse neuronal populations has been a fundamental biological problem since the 19(th) century. Classical histological methods revealed that postmitotic neurons are produced in a precise temporal and spatial order from germinal cells lining the cerebral ventricles. In the 20(th) century, DNA labeling and histo- and immunohistochemistry helped to distinguish the subtypes of dividing cells and delineate their locations in the ventricular and subventricular zones. Recently, genetic and cell biological methods have provided insights into sequential gene expression and molecular and cellular interactions that generate heterogeneous populations of NSCs leading to specific neuronal classes. This precisely regulated developmental process does not tolerate significant in vivo deviation, making replacement of adult neurons by NSCs during pathology a colossal challenge. In contrast, utilizing the trophic factors emanating from the NSC or their derivatives to slow down deterioration or prevent death of degenerating neurons may be a more feasible strategy. Copyright © 2011 Elsevier Inc. All rights reserved.
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              3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

              Alzheimer’s disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.
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                Author and article information

                Journal
                Int J Mol Med
                Int. J. Mol. Med
                IJMM
                International Journal of Molecular Medicine
                D.A. Spandidos
                1107-3756
                1791-244X
                February 2018
                30 November 2017
                30 November 2017
                : 41
                : 2
                : 783-790
                Affiliations
                [1 ]Korea Institute of Toxicology, Daejeon 34114
                [2 ]Department of Human and Environmental Toxicology, Korea University of Science and Technology, Daejeon 34113
                [3 ]Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141
                [4 ]Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology, School of Bioscience, Korea University of Science and Technology, Daejeon 34113
                [5 ]Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
                Author notes
                Correspondence to: Dr Mi-Young Son or Dr Janghwan Kim, Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahangno, Yuseong-gu, Daejeon 34141, Republic of Korea, E-mail: myson@ 123456kribb.re.kr , E-mail: janghwan.kim@ 123456kribb.re.kr

                *Contributed equally

                Article
                ijmm-41-02-0783
                10.3892/ijmm.2017.3298
                5752237
                29207026
                e35e196a-3710-467a-9710-c4813945e3d7
                Copyright: © Oh et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 07 August 2017
                : 29 November 2017
                Categories
                Articles

                neural stem cell,neural sphere,human embryonic stem cell,rencell,microarray,differentiation

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