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      Pluripotent Stem Cells for the Study of CNS Development

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          The mammalian central nervous system is a complex neuronal network consisting of a diverse array of cellular subtypes generated in a precise spatial and temporal pattern throughout development. Achieving a greater understanding of the molecular and genetic mechanisms that direct a relatively uniform population of neuroepithelial progenitors into diverse neuronal subtypes remains a significant challenge. The advent of pluripotent stem cell (PSC) technology allows researchers to generate diverse neural populations in vitro. Although the primary focus of PSC-derived neural cells has been their therapeutic potential, utilizing PSCs to study neurodevelopment is another frequently overlooked and equally important application. In this review, we explore the potential for utilizing PSCs to study neural development. We introduce the types of neurodevelopmental questions that PSCs can help to address, and we discuss the different strategies and technologies that researchers use to generate diverse subtypes of PSC-derived neurons. Additionally, we highlight the derivation of several thoroughly characterized neural subtypes; spinal motoneurons, midbrain dopaminergic neurons and cortical neurons. We hope that this review encourages researchers to develop innovative strategies for using PSCs for the study of mammalian, and specifically human, neurodevelopment.

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          Most cited references 108

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

            Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.
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              Induced pluripotent stem cell lines derived from human somatic cells.

              Somatic cell nuclear transfer allows trans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to an undifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Such induced pluripotent human cell lines should be useful in the production of new disease models and in drug development, as well as for applications in transplantation medicine, once technical limitations (for example, mutation through viral integration) are eliminated.

                Author and article information

                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Research Foundation
                12 October 2011
                : 4
                1simpleDepartment of Psychiatry, Weill Cornell Medical College New York, NY, USA
                2simpleProgram in Neuroscience, Weill Cornell Medical College New York, NY, USA
                Author notes

                Edited by: Alistair N. Garratt, Max Delbrück Center for Molecular Medicine, Germany

                Reviewed by: Ye He, University of California San Francisco, USA; Smita Jha, Baylor College of Medicine, USA

                *Correspondence: Stewart A. Anderson, Department of Psychiatry, Weill Cornell Medical College, Box 244, 1300 York Avenue, New York, NY 10065, USA. e-mail: saa2007@

                This article was submitted to Frontiers in Molecular Neuroscience, a specialty of Frontiers in Molecular Neuroscience.

                Copyright © 2011 Petros, Tyson and Anderson.

                This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 109, Pages: 12, Words: 11313
                Review Article


                stem cells, pluripotent, nervous system, embryonic, derivation, development, neurons


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