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      Reprogramming and transdifferentiation for cardiovascular development and regenerative medicine: where do we stand?

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          Abstract

          Heart disease remains a leading cause of mortality and a major worldwide healthcare burden. Recent advances in stem cell biology have made it feasible to derive large quantities of cardiomyocytes for disease modeling, drug development, and regenerative medicine. The discoveries of reprogramming and transdifferentiation as novel biological processes have significantly contributed to this paradigm. This review surveys the means by which reprogramming and transdifferentiation can be employed to generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and induced cardiomyocytes (iCMs). The application of these patient-specific cardiomyocytes for both in vitro disease modeling and in vivo therapies for various cardiovascular diseases will also be discussed. We propose that, with additional refinement, human disease-specific cardiomyocytes will allow us to significantly advance the understanding of cardiovascular disease mechanisms and accelerate the development of novel therapeutic options.

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          Most cited references106

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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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            Naive and primed pluripotent states.

            After maternal predetermination gives way to zygotic regulation, a ground state is established within the mammalian embryo. This tabula rasa for embryogenesis is present only transiently in the preimplantation epiblast. Here, we consider how unrestricted cells are first generated and then prepared for lineage commitment. We propose that two phases of pluripotency can be defined: naive and primed. This distinction extends to pluripotent stem cells derived from embryos or by molecular reprogramming ex vivo.
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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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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                emmm
                EMBO Molecular Medicine
                John Wiley & Sons, Ltd (Chichester, UK )
                1757-4676
                1757-4684
                September 2015
                16 July 2015
                : 7
                : 9
                : 1090-1103
                Affiliations
                [1 ]Stanford Cardiovascular Institute, Stanford University School of Medicine Stanford, CA, USA
                [2 ]Department of Medicine, Division of Cardiology, Stanford University School of Medicine Stanford, CA, USA
                [3 ]Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine Stanford, CA, USA
                [4 ]Max Delbrück Center Berlin, Germany
                [5 ]Berlin Institute of Health Berlin, Germany
                Author notes
                * Corresponding author. Tel: +1 650 736 2246; E-mail: joewu@ 123456stanford.edu
                Article
                10.15252/emmm.201504395
                4568945
                26183451
                1a0c25bf-63d0-4d5b-a0b9-2bef789dadca
                © 2015 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 March 2015
                : 07 June 2015
                : 15 June 2015
                Categories
                Reviews

                Molecular medicine
                cardiomyocytes,disease modeling,genome editing,human induced pluripotent stem cells,tissue engineering

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