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Stem Cell Therapy for Sensorineural Hearing Loss, Still Alive?

Journal of Audiology & Otology

The Korean Audiological Society

Cochlea, Stem cell, Hair cell

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      Abstract

      In mammals, the auditory system, which includes the cochlea, has a very complex structure harboring many types of cells performing different functions. Among these cells are the auditory hair cells (HCs), which are terminally and well differentiated unique cells which have lost their regenerative potential after development. The auditory HCs are easily damaged by aging as well as during episodes of ototoxicity and acoustic trauma. HCs damages typically occur in the early stage of injury and can result a permanent hearing loss. Recently, there have been tremendous developments from stem cells (SCs) research involving sensorineural hearing loss, but several limitations and obstacles persist in allowing these developments from continuing onto clinical applications. This review discusses the recent advances in SC research in sensorineural hearing loss with the subsequent sections discussing the possible hurdles and limitations that currently preclude their clinical application.

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      Most cited references 27

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      Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.

      In the mammalian auditory system, sensory cell loss resulting from aging, ototoxic drugs, infections, overstimulation and other causes is irreversible and leads to permanent sensorineural hearing loss. To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1, a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal. The data suggest a new therapeutic approach based on expressing crucial developmental genes for cellular and functional restoration in the damaged auditory epithelium and other sensory systems.
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        Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells.

        Sensory hair cells of the mammalian organ of Corti in the inner ear do not regenerate when lost as a consequence of injury, disease, or age-related deafness. This contrasts with other vertebrates such as birds, where the death of hair cells causes surrounding supporting cells to re-enter the cell cycle and give rise to both new hair cells and supporting cells. It is not clear whether the lack of mammalian hair cell regeneration is due to an intrinsic inability of supporting cells to divide and differentiate or to an absence or blockade of regenerative signals. Here we show that post-mitotic supporting cells purified from the postnatal mouse cochlea retain the ability to divide and trans-differentiate into new hair cells in culture. Furthermore, we show that age-dependent changes in supporting cell proliferative capacity are due in part to changes in the ability to downregulate the cyclin-dependent kinase inhibitor p27(Kip1) (also known as Cdkn1b). These results indicate that postnatal mammalian supporting cells are potential targets for therapeutic manipulation.
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          Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

          The inner ear contains sensory epithelia that detect head movements, gravity and sound. It is unclear how to derive these sensory epithelia from pluripotent stem cells, a process which will be critical for modeling inner ear disorders or developing cell-based therapies for profound hearing loss and balance disorders 1,2 . To date, attempts to derive inner ear mechanosensitive hair cells and sensory neurons have resulted in inefficient or incomplete phenotypic conversion of stem cells into inner ear-like cells 3–7 . A key insight lacking from these previous studies is the importance of the non-neural and pre-placodal ectoderm, two critical precursors during inner ear development 8–11 . Here we report the step-wise differentiation of inner ear sensory epithelia from mouse embryonic stem cells (ESCs) in three-dimensional culture 12,13 . We show that by recapitulating in vivo development with precise temporal control of BMP, TGFβ and FGF signaling, ESC aggregates transform sequentially into non-neural, pre-placodal and otic placode-like epithelia. Remarkably, in a self-organized process that mimics normal development, vesicles containing prosensory cells emerge from the presumptive otic placodes and give rise to hair cells bearing stereocilia bundles and a kinocilium. Moreover, these stem cell-derived hair cells exhibit functional properties of native mechanosensitive hair cells and form specialized synapses with sensory neurons that have also arisen from ESCs in the culture. Finally, we demonstrate how these vesicles are structurally and biochemically comparable to developing vestibular end organs. Our data thus establish a novel in vitro model of inner ear differentiation that can be used to gain deeper insight into inner ear development and disorder.
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            Author and article information

            Affiliations
            Department of Otolaryngology-Head and Neck Surgery, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon, Korea.
            Author notes
            Address for correspondence: Yong-Ho Park, MD, PhD. Department of Otolaryngology-Head and Neck Surgery, Brain Research Institute, College of Medicine, Chungnam National University, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. Tel +82-42-280-7697, Fax +82-42-253-4059, parkyh@ 123456cnu.ac.kr
            Journal
            J Audiol Otol
            J Audiol Otol
            JAO
            Journal of Audiology & Otology
            The Korean Audiological Society
            2384-1621
            2384-1710
            September 2015
            16 September 2015
            : 19
            : 2
            : 63-67
            4582452
            10.7874/jao.2015.19.2.63
            Copyright © 2015 The Korean Audiological Society

            This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Funding
            Funded by: Chungnam National University Hospital
            Categories
            Review
            Keywords:

            Comments

            Good review of unresolved obstacles toward hearing restoration with emphasis on viability of precursors in SM.

            2015-11-26 17:58 UTC
            +1

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