https://www.nature.com/articles/s41598-020-76553-w
https://pubmed.ncbi.nlm.nih.gov/33203940/
Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea
www.HearingLossTreatmentReport.com
https://www.nature.com/articles/s41598-020-76553-w
https://pubmed.ncbi.nlm.nih.gov/33203940/
Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea
https://www.jneurosci.org/content/early/2020/07/17/JNEUROSCI.0937-20.2020
https://www.ncbi.nlm.nih.gov/pubmed/32690619?dopt=Abstract
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Age-related hearing loss is dominated by damage to inner ear sensory cells, not the cellular battery that powers them.
J Neurosci. 2020 Jul 20;:
Authors: Wu PZ, O’Malley JT, de Gruttola V, Liberman MC
Abstract
Age-related hearing loss arises from irreversible damage in the inner ear, where sound is transduced into electrical signals. Prior human studies suggested that sensory-cell loss is rarely the cause; correspondingly, animal work has implicated the stria vascularis, the cellular “battery” driving the amplification of sound by hair cell “motors”. Here, quantitative microscopic analysis of hair cells, auditory nerve fibers and strial tissues in 120 human inner ears obtained at autopsy, most of whom had recent audiograms in their medical records, shows that the degree of hearing loss is well predicted from the amount of hair cell loss and that inclusion of strial damage does not improve the prediction. Although many aging ears showed significant strial degeneration throughout the cochlea, our statistical models suggest that, by the time strial tissues are lost, hair cell death is so extensive that the loss of battery is no longer important to pure-tone thresholds and that audiogram slope is not diagnostic for strial degeneration. These data comprise the first quantitative survey of hair cell death in normal-aging human cochleas, and reveal unexpectedly severe hair cell loss in low-frequency cochlear regions, and dramatically greater loss in high-frequency regions than seen in any aging animal model. Comparison of normal-aging ears to an age-matched group with acoustic-overexposure history suggests that a lifetime of acoustic overexposure is to blame.Significance StatementThis report upends dogma about the causes of age-related hearing loss. Our analysis of over 120 autopsy specimens shows that inner-ear sensory cell loss can largely explain the audiometric patterns in aging, with minimal contribution from the stria vascularis, the “battery” that powers the inner ear, previously viewed as the major locus of age-related hearing dysfunction. Predicting inner ear damage from the audiogram is critical, now that clinical trials of therapeutics designed to regrow hair cells are underway. Our data also show that hair cell degeneration in aging humans is dramatically worse than that in aging animals, suggesting that the high-frequency hearing losses that define human presbycusis reflect avoidable contributions of chronic ear abuse to which aging animals are not exposed.
PMID: 32690619 [PubMed – as supplied by publisher]
https://www.biorxiv.org/content/10.1101/2020.07.01.183269v1.full
https://www.researchgate.net/publication/342660327_An_Antibody_to_RGMa_Promotes_Regeneration_of_Cochlear_Synapses_after_Noise_Exposure
An Antibody to RGMa Promotes Regeneration of Cochlear Synapses after Noise Exposure
SUMMARY
Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.
https://www.sciencedaily.com/releases/2020/07/200701134242.htm
A simpler way to make sensory hearing cells
Date:
July 1, 2020
Source:
Keck School of Medicine of USC
Summary:
Scientists are whispering the secrets of a simpler way to generate the sensory cells of the inner ear. Their approach uses direct reprogramming to produce sensory cells known as ‘hair cells,’ due to their hair-like protrusions that sense sound waves.
https://elifesciences.org/articles/55249
https://www.ncbi.nlm.nih.gov/pubmed/32602462?dopt=Abstract
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Generation of inner ear hair cells by direct lineage conversion of primary somatic cells.
Elife. 2020 Jun 30;9:
Authors: Menendez L, Trecek T, Gopalakrishnan S, Tao L, Markowitz AL, Yu HV, Wang X, Llamas J, Huang C, Lee J, Kalluri R, Ichida J, Segil N
Abstract
The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.
PMID: 32602462 [PubMed – in process]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364385/
Hair cell regeneration from inner ear progenitors in the mammalian cochlea
Shasha Zhang,1 Ruiying Qiang,1 Ying Dong,1 Yuan Zhang,1 Yin Chen,5 Han Zhou,5 Xia Gao,5 and Renjie Chai1,2,3,4,5
Author information Article notes Copyright and License information Disclaimer
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Abstract
Cochlear hair cells (HCs) are the mechanoreceptors of the auditory system, and because these cells cannot be spontaneously regenerated in adult mammals, hearing loss due to HC damage is permanent. However, cochleae of neonatal mice harbor some progenitor cells that retain limited ability to give rise to new HCs in vivo. Here we review the regulatory factors, signaling pathways, and epigenetic factors that have been reported to play roles in HC regeneration in the neonatal mammalian cochlea.
Keywords: Cochlea, inner ear progenitor, hair cell regeneration, transcription factor, signaling pathway
https://dev.biologists.org/content/146/17/dev177188
https://www.ncbi.nlm.nih.gov/pubmed/31477580?dopt=Abstract
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Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration.
Development. 2019 09 02;146(17):
Authors: Roccio M, Edge ASB
Abstract
The development of therapeutic interventions for hearing loss requires fundamental knowledge about the signaling pathways controlling tissue development as well as the establishment of human cell-based assays to validate therapeutic strategies ex vivo Recent advances in the field of stem cell biology and organoid culture systems allow the expansion and differentiation of tissue-specific progenitors and pluripotent stem cells in vitro into functional hair cells and otic-like neurons. We discuss how inner ear organoids have been developed and how they offer for the first time the opportunity to validate drug-based therapies, gene-targeting approaches and cell replacement strategies.
PMID: 31477580 [PubMed – indexed for MEDLINE]
https://www.sciencedirect.com/science/article/pii/S0163725819300774?via%3Dihub
https://www.ncbi.nlm.nih.gov/pubmed/31075354?dopt=Abstract
New molecular therapies for the treatment of hearing loss.
Pharmacol Ther. 2019 May 07;:
Authors: Ma Y, Wise AK, Shepherd RK, Richardson RT
Abstract
An estimated 466 million people suffer from hearing loss worldwide. Sensorineural hearing loss is characterized by degeneration of key structures of the sensory pathway in the cochlea such as the sensory hair cells, the primary auditory neurons and their synaptic connection to the hair cells – the ribbon synapse. Various strategies to protect or regenerate these sensory cells and structures are the subject of intensive research. Yet despite recent advances in our understandings of the capacity of the cochlea for repair and regeneration there are currently no pharmacological or biological interventions for hearing loss. Current research focusses on localized cochlear drug, gene and cell-based therapies. One of the more promising drug-based therapies is based on neurotrophic factors for the repair of the ribbon synapse after noise exposure, as well as preventing loss of primary auditory neurons and regrowth of the auditory neuron fibers after severe hearing loss. Drug therapy delivery technologies are being employed to address the specific needs of neurotrophin and other therapies for hearing loss that include the need for high doses, long-term delivery, localised or cell-specific targeting and techniques for their safe and efficacious delivery to the cochlea. Novel biomaterials are enabling high payloads of drugs to be administered to the cochlea with subsequent slow-release properties that are proving to be beneficial for treating hearing loss. In parallel, new gene therapy technologies are addressing the need for cell specificity and high efficacy for the treatment of both genetic and acquired hearing loss with promising reports of hearing recovery. Some biomaterials and cell therapies are being used in conjunction with the cochlear implant ensuring therapeutic benefit to the primary neurons during electrical stimulation. This review will introduce the auditory system, hearing loss and the potential for repair and regeneration in the cochlea. Drug delivery to the cochlea will then be reviewed, with a focus on new biomaterials, gene therapy technologies, cell therapy and the use of the cochlear implant as a vehicle for drug delivery. With the current pre-clinical research effort into therapies for hearing loss, including clinical trials for gene therapy, the future for the treatment for hearing loss is looking bright.
PMID: 31075354 [PubMed – as supplied by publisher]