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      Genomic Instability of iPSCs: Challenges Towards Their Clinical Applications

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          Abstract

          Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cells generated directly from mature cells through the introduction of key transcription factors. iPSCs can be propagated and differentiated into many cell types in the human body, holding enormous potential in the field of regenerative medicine. However, genomic instability of iPSCs has been reported with the advent of high-throughput technologies such as next-generation sequencing. The presence of genetic variations in iPSCs has raised serious safety concerns, hampering the advancement of iPSC-based novel therapies. Here we summarize our current knowledge on genomic instability of iPSCs, with a particular focus on types of genetic variations and their origins. Importantly, it remains elusive whether genetic variations in iPSCs can be an actual risk factor for adverse effects including malignant outgrowth. Furthermore, we discuss novel approaches to generate iPSCs with fewer genetic variations. Lastly, we outline the safety issues and monitoring strategies of iPSCs in clinical settings.

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          Most cited references69

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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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            Mutation and cancer: statistical study of retinoblastoma.

            A Knudson (1971)
            Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
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              Generation of induced pluripotent stem cells using recombinant proteins.

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                Author and article information

                Contributors
                yasuhiro.murakawa@riken.jp
                Journal
                Stem Cell Rev
                Stem Cell Rev
                Stem Cell Reviews
                Springer US (New York )
                1550-8943
                1558-6804
                5 September 2016
                5 September 2016
                2017
                : 13
                : 1
                : 7-16
                Affiliations
                [1 ]Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa Japan
                [2 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Ophthalmology, , Osaka University Graduate School of Medicine, ; Suita, Osaka Japan
                [3 ]RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama Japan
                Article
                9680
                10.1007/s12015-016-9680-6
                5346115
                27592701
                ed42bcb1-8ec4-43d7-9dcf-1ead19302b38
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science, and Technology;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science, and Technology;
                Categories
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                © Springer Science+Business Media New York 2017

                Molecular medicine
                ipscs,genomic instability,mutation,regenerative medicine,clinical application
                Molecular medicine
                ipscs, genomic instability, mutation, regenerative medicine, clinical application

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