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      Stem Cell Therapy for Sensorineural Hearing Loss, Still Alive?

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      Author(s):
      Publication date (Electronic):
      Journal: Journal of Audiology & Otology
      Publisher: The Korean Audiological Society
      Keywords: 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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          Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.

          Kohei Kawamoto, Yehoash Raphael, Ryosei Minoda … (2005)
          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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            Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

            Karl Koehler, Andrew Mikosz, Andrei I. Molosh … (2013)
            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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              Restoration of auditory evoked responses by human ES cell-derived otic progenitors

              Wei Chen, Nopporn Jongkamonwiwat, Leila Abbas … (2012)
              Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of a particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells 1 , is responsible for a substantial proportion of patients with hearing impairment 2 . While the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss since poor innervation limits the prospective performance of an implant 3 . Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here, we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory evoked response (ABR) thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Audiol Otol
                Journal ID (iso-abbrev): J Audiol Otol
                Journal ID (publisher-id): JAO
                Title: Journal of Audiology & Otology
                Publisher: The Korean Audiological Society
                ISSN (Print): 2384-1621
                ISSN (Electronic): 2384-1710
                Publication date (Print): September 2015
                Publication date (Electronic): 16 September 2015
                Volume: 19
                Issue: 2
                Pages: 63-67
                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
                Article
                DOI: 10.7874/jao.2015.19.2.63
                PMC ID: 4582452
                SO-VID: 44bc44ca-ce7c-457d-9d98-69532933ec5a
                Copyright © Copyright © 2015 The Korean Audiological Society
                License:

                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.

                History
                Date received : 14 August 2015
                Date revision received : 15 August 2015
                Date accepted : 18 August 2015
                Funding
                Funded by: Chungnam National University Hospital
                Categories
                Subject: Review

                Keywords: cochlea,stem cell,hair cell
                Data availability:
                Keywords: cochlea, stem cell, hair cell

                Comments

                wrote:

                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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