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      Early‐stage development of human induced pluripotent stem cell‐derived neurons

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          Abstract

          Recent advances in human induced pluripotent stem cells (hiPSCs) offer new possibilities for biomedical research and clinical applications. Differentiated neurons from hiPSCs are expected to be useful for developing novel methods of treatment for various neurological diseases. However, the detailed process of functional maturation of hiPSC‐derived neurons (hiPS neurons) remains poorly understood. This study analyzes development of hiPS neurons, focusing specifically on early developmental stages through 48 hr after cell seeding; development was compared with that of primary cultured neurons derived from the rat hippocampus. At 5 hr after cell seeding, neurite formation occurs in a similar manner in both neuronal populations. However, very few neurons with axonal polarization were observed in the hiPS neurons even after 48 hr, indicating that hiPS neurons differentiate more slowly than rat neurons. We further investigated the elongation speed of axons and found that hiPS neuronal axons were slower. In addition, we characterized the growth cones. The localization patterns of skeletal proteins F‐actin, microtubule, and drebrin were similar to those of rat neurons, and actin depolymerization by cytochalasin D induced similar changes in cytoskeletal distribution in the growth cones between hiPS neurons and rat neurons. These results indicate that, during the very early developmental stage, hiPS neurons develop comparably to rat hippocampal neurons with regard to axonal differentiation, but the growth of axons is slower. © 2015 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

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          Most cited references26

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          The establishment of polarity by hippocampal neurons in culture.

          By the end of the first week in culture, hippocampal neurons have established a single axon and several dendrites. These 2 classes of processes differ in their morphology, in their molecular composition, and in their synaptic polarity (Bartlett and Banker, 1984a, b; Caceres et al., 1984). We examined the events during the first week in culture that lead to the establishment of this characteristic form. Hippocampal cells were obtained from 18 d fetal rats, plated onto polylysine-treated coverslips, and maintained in a serum-free medium. The development of individual cells was followed by sequential photography at daily intervals until both axons and dendrites had been established; identification of the processes was confirmed by immunostaining for MAP2, a dendritic marker. Time-lapse video recording was used to follow the early stages of process formation. Hippocampal neurons acquired their characteristic form by a stereotyped sequence of developmental events. The cells first established several, apparently identical, short processes. After several hours, one of the short processes began to grow very rapidly; it became the axon. The remaining processes began to elongate a few days later and grew at a much slower rate. They became the cell's dendrites. Neurons that arose following mitosis in culture underwent this same sequence of developmental events. In a few instances, 2 processes from a cell exhibited the rapid growth typical of axons, but only one maintained this growth; the other retracted and became a dendrite. Axons branched primarily by the formation of collaterals, not by bifurcation of growth cones. As judged by light microscopy, processes are not specified as axons or dendrites when they arise. The first manifestation of neuronal polarity is the acquisition of axonal characteristics by one of the initial processes; subsequently the remaining processes become dendrites.
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            Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.

            The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to α-synuclein (αsyn), a key protein involved in Parkinson's disease (PD). We generated cortical neurons from iPS cells of patients harboring αsyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of αsyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.
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              Neuronal polarity.

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                Author and article information

                Journal
                J Neurosci Res
                J. Neurosci. Res
                10.1002/(ISSN)1097-4547
                JNR
                Journal of Neuroscience Research
                John Wiley and Sons Inc. (Hoboken )
                0360-4012
                1097-4547
                08 September 2015
                December 2015
                : 93
                : 12 ( doiID: 10.1002/jnr.v93.12 )
                : 1804-1813
                Affiliations
                [ 1 ] Department of Neurobiology and BehaviorGunma University Graduate School of Medicine Maebashi GunmaJapan
                [ 2 ] Division of PharmacologyNational Institute of Health Sciences TokyoJapan
                Author notes
                [*] [* ]Correspondence to: Tomoaki Shirao, MD, PhD, Professor and Chairman, Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, 3‐39‐22 Showa‐machi, Maebashi, Gunma 371‐8511, Japan. E‐mail: tshirao@ 123456gunma-u.ac.jp
                [†]

                SIGNIFICANCE: Human induced pluripotent stem cell‐derived neurons (hiPS neurons) offer new possibilities for biomedical research and clinical applications. Because humans have higher brain functions, differentiation of human neurons might have characteristics different from those of nonhuman neurons studied to date. This study focuses on early development of hiPS neurons and compares the development of cultured rat hippocampal neurons. Results indicate that morphological development of rat and human neurons before axonal polarization is similar. However, morphological development of axons in the hiPS neurons develops more slowly, showing especially slow elongation of the axon. This study also shows that the growth cone of hiPS neurons functions similarly to that of rat neurons.

                Article
                JNR23666
                10.1002/jnr.23666
                5049656
                26346430
                53a17fc3-9b6e-4344-b3d8-1779ec3149e7
                © 2015 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

                This is an open access article 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
                : 25 May 2015
                : 03 August 2015
                : 22 August 2015
                Page count
                Pages: 11
                Funding
                Funded by: MHLW Health and Labor Sciences Research Grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices
                Funded by: Japan Society for the Promotion of Science (JSPS)
                Award ID: 26860980
                Award ID: 26430063
                Award ID: 15K14344
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                jnr23666
                December 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:04.10.2016

                Neurosciences
                axonal development,growth cones,cytoskeletal proteins
                Neurosciences
                axonal development, growth cones, cytoskeletal proteins

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