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      On the Viability and Potential Value of Stem Cells for Repair and Treatment of Central Neurotrauma: Overview and Speculations

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          Abstract

          Central neurotrauma, such as spinal cord injury or traumatic brain injury, can damage critical axonal pathways and neurons and lead to partial to complete loss of neural function that is difficult to address in the mature central nervous system. Improvement and innovation in the development, manufacture, and delivery of stem-cell based therapies, as well as the continued exploration of newer forms of stem cells, have allowed the professional and public spheres to resolve technical and ethical questions that previously hindered stem cell research for central nervous system injury. Recent in vitro and in vivo models have demonstrated the potential that reprogrammed autologous stem cells, in particular, have to restore functionality and induce regeneration—while potentially mitigating technical issues of immunogenicity, rejection, and ethical issues of embryonic derivation. These newer stem-cell based approaches are not, however, without concerns and problems of safety, efficacy, use and distribution. This review is an assessment of the current state of the science, the potential solutions that have been and are currently being explored, and the problems and questions that arise from what appears to be a promising way forward (i.e., autologous stem cell-based therapies)—for the purpose of advancing the research for much-needed therapeutic interventions for central neurotrauma.

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          Most cited references277

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          Direct conversion of fibroblasts to functional neurons by defined factors

          Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2, and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials, and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modeling, and regenerative medicine.
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            Human induced pluripotent stem cells free of vector and transgene sequences.

            Reprogramming differentiated human cells to induced pluripotent stem (iPS) cells has applications in basic biology, drug development, and transplantation. Human iPS cell derivation previously required vectors that integrate into the genome, which can create mutations and limit the utility of the cells in both research and clinical applications. We describe the derivation of human iPS cells with the use of nonintegrating episomal vectors. After removal of the episome, iPS cells completely free of vector and transgene sequences are derived that are similar to human embryonic stem (ES) cells in proliferative and developmental potential. These results demonstrate that reprogramming human somatic cells does not require genomic integration or the continued presence of exogenous reprogramming factors and removes one obstacle to the clinical application of human iPS cells.
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              Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

              Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                13 August 2018
                2018
                : 9
                : 602
                Affiliations
                [1] 1Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center , Washington, DC, United States
                [2] 2Department of Oncology, Georgetown University Medical Center , Washington, DC, United States
                [3] 3Departments of Neurology and Biochemistry, Georgetown University Medical Center , Washington, DC, United States
                Author notes

                Edited by: Vassilis E. Koliatsos, Johns Hopkins University, United States

                Reviewed by: Martin L. Doughty, Uniformed Services University, United States; Hassan Azari, Shiraz University of Medical Sciences, Iran; Dong Sun, Virginia Commonwealth University, United States

                *Correspondence: James Giordano James.giordano@ 123456georgetown.edu

                This article was submitted to Neurotrauma, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2018.00602
                6099099
                30150968
                26d33dd4-8fa3-4cfe-a6c3-d1251acd650b
                Copyright © 2018 Wu, FitzGerald and Giordano.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 January 2018
                : 06 July 2018
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 390, Pages: 24, Words: 22433
                Funding
                Funded by: National Center for Advancing Translational Sciences 10.13039/100006108
                Award ID: UL1TR001409
                Categories
                Neurology
                Review

                Neurology
                nervous system trauma,neural stem cells,autologous transplantation,regeneration,cell and tissue based therapy,spinal cord injury,traumatic brain injury

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