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      Renewed proliferation in adult mouse cochlea and regeneration of hair cells

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          Abstract

          The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage to inner ear generally leads to permanent hearing loss in humans. Here, we present that reprogramming of the adult inner ear induces renewed proliferation and regeneration of inner ear cell types. Co-activation of cell cycle activator Myc and inner ear progenitor gene Notch1 induces robust proliferation of diverse adult cochlear sensory epithelial cell types. Transient MYC and NOTCH activities enable adult supporting cells to respond to transcription factor Atoh1 and efficiently transdifferentiate into hair cell-like cells. Furthermore, we uncover that mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells take up the styryl dye FM1-43 and are likely to form connections with adult spiral ganglion neurons, supporting that Myc and Notch1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs.

          Abstract

          The adult mammalian inner ear cells cannot regenerate nor proliferate. Here, the authors show that co-activation of Myc and NOTCH pathways can stimulate proliferation of inner ear sensory epithelial cells, which can be induced to become hair cell-like cells in vitro and in vivo.

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          Most cited references66

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          Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.

          The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
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            Induced pluripotent stem cells generated without viral integration.

            Pluripotent stem cells have been generated from mouse and human somatic cells by viral expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc. A major limitation of this technology is the use of potentially harmful genome-integrating viruses. We generated mouse induced pluripotent stem (iPS) cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS (adeno-iPS) cells show DNA demethylation characteristic of reprogrammed cells, express endogenous pluripotency genes, form teratomas, and contribute to multiple tissues, including the germ line, in chimeric mice. Our results provide strong evidence that insertional mutagenesis is not required for in vitro reprogramming. Adenoviral reprogramming may provide an improved method for generating and studying patient-specific stem cells and for comparing embryonic stem cells and iPS cells.
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              Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline.

              Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.
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                Author and article information

                Contributors
                Zheng-Yi_Chen@meei.harvard.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                4 December 2019
                4 December 2019
                2019
                : 10
                : 5530
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Techology and Program in Neuroscience, , Harvard Medical School, ; Boston, MA 02115 USA
                [2 ]ISNI 0000 0000 8800 3003, GRID grid.39479.30, Eaton-Peabody Laboratory, , Massachusetts Eye and Ear Infirmary, ; 243 Charles St., Boston, MA 02114 USA
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Biomedcial Sciences, , Fudan University, ; 200031 Shanghai, China
                [4 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, NHC Key Laboratory of Hearing Medicine, , Fudan University, ; Shanghai, 200031 China
                [5 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Neurobiology and Howard Hughes Medical Institute, , Harvard Medical School, ; Boston, MA 02115 USA
                [6 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Department of Otolaryngology, , University of Miami School of Medicine, ; Miami, FL 33136 USA
                [7 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, , Massachusetts General Hospital, ; Boston, MA 02114 USA
                [8 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, ; Cambridge, MA 02138 USA
                [9 ]ISNI 0000 0001 2167 1581, GRID grid.413575.1, Howard Hughes Medical Institute, ; Chevy Chase, MD 20815 USA
                Author information
                http://orcid.org/0000-0001-5811-5386
                http://orcid.org/0000-0002-1452-4193
                Article
                13157
                10.1038/s41467-019-13157-7
                6892913
                31797926
                e5598024-ab5b-4950-9a3e-ed4f03e73118
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 14 November 2018
                : 13 October 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000055, U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD);
                Award ID: R01DC006908
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000005, U.S. Department of Defense (United States Department of Defense);
                Award ID: W81XWH1810331
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                cell signalling,cell proliferation,reprogramming,development
                Uncategorized
                cell signalling, cell proliferation, reprogramming, development

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