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Cell Death & Disease Sep 2023Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic... (Review)
Review
Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic nerve (VIII cranial nerve), in the cochlea are present the hair cells, the spiral ganglion neurons, the glia-like supporting cells, and the Schwann cells (SCs), which alterations have been considered cause of HL. Notably, a benign SC-derived tumor of the acoustic nerve, named vestibular schwannoma (VS), has been indicated as cause of HL. Importantly, SCs are the main glial cells ensheathing axons and forming myelin in the peripheral nerves. Following an injury, the SCs reprogram, expressing some stemness features. Despite the mechanisms and factors controlling their biological processes (i.e., proliferation, migration, differentiation, and myelination) have been largely unveiled, their role in VS and HL was poorly investigated. In this review, we enlighten some of the mechanisms at the base of SCs transformation, VS development, and progression, likely leading to HL, and we pose great attention on the environmental factors that, in principle, could contribute to HL onset or progression. Combining the biomolecular bench-side approach to the clinical bedside practice may be helpful for the diagnosis, prediction, and therapeutic approach in otology.
Topics: Humans; Neuroma, Acoustic; Hearing Loss; Deafness; Schwann Cells; Neuroglia
PubMed: 37741837
DOI: 10.1038/s41419-023-06141-z -
Journal of Controlled Release :... Dec 2023Noise-induced hearing loss (NIHL) is one of the most prevalent acquired sensorineural hearing loss etiologies and is characterized by the loss of cochlear hair cells,...
Noise-induced hearing loss (NIHL) is one of the most prevalent acquired sensorineural hearing loss etiologies and is characterized by the loss of cochlear hair cells, synapses, and nerve terminals. Currently, there are no agents available for the treatment of NIHL because drug delivery to the inner ear is greatly limited by the blood-labyrinth barrier. In this study, we used mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) as nanoscale vehicles to deliver brain-derived neurotrophic factor (BDNF) and evaluated their protective effects in a mouse model of NIHL. Following intravenous administration, BDNF-loaded sEVs (BDNF-sEVs) efficiently increased the expression of BDNF protein in the cochlea. Systemic application of sEVs and BDNF-sEVs significantly attenuated noise-induced cochlear hair cell loss and NIHL in CBA/J mice. BDNF-sEVs also alleviated noise-induced loss of inner hair cell ribbon synapses and cochlear nerve terminals. In cochlear explants, sEVs and BDNF-sEVs effectively protected hair cells against HO-induced cell loss. Additionally, BDNF-sEVs remarkably ameliorated HO-induced oxidative stress, cell apoptosis, and cochlear nerve terminal degeneration. Transcriptomic analysis revealed that many mRNAs and miRNAs were involved in the protective actions of BDNF-sEVs against oxidative stress. Collectively, our findings reveal a novel therapeutic strategy of MSC-sEVs-mediated BDNF delivery for the treatment of NIHL.
Topics: Animals; Mice; Brain-Derived Neurotrophic Factor; Cochlea; Extracellular Vesicles; Hearing Loss, Noise-Induced; Hydrogen Peroxide; Mice, Inbred CBA
PubMed: 37939851
DOI: 10.1016/j.jconrel.2023.11.007 -
Neuro-oncology Dec 2023Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many...
BACKGROUND
Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.
METHODS
We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.
RESULTS
We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.
CONCLUSIONS
We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.
Topics: Humans; INDEL Mutation; Transcriptional Activation; Neurilemmoma; Neuroma, Acoustic; Mutation; Nerve Sheath Neoplasms; SOXE Transcription Factors
PubMed: 37436963
DOI: 10.1093/neuonc/noad121 -
CoDAS 2023To identify the pathophysiological definitions adopted by studies investigating "cochlear synaptopathy" (CS) and "hidden hearing loss" (HHL). (Review)
Review
PURPOSE
To identify the pathophysiological definitions adopted by studies investigating "cochlear synaptopathy" (CS) and "hidden hearing loss" (HHL).
RESEARCH STRATEGIES
The combination of keywords "Auditory Synaptopathy" or "Neuronal Synaptopathy" or "Hidden Hearing Loss" with "etiology" or "causality" or "diagnosis" was used in the databases EMBASE, Pubmed (MEDLINE), CINAHL (EBSCO), and Web of Science.
SELECTION CRITERIA
Studies that investigated CS or HHL in humans using behavioral and/or electrophysiological procedures were included.
DATA ANALYSIS
Data analysis and extraction were performed with regard to terminology, definitions, and population.
RESULTS
49 articles were included. Of these, 61.2% used the CS terminology, 34.7% used both terms, and 4.1% used HHL. The most-studied conditions were exposure to noise and tinnitus.
CONCLUSION
CS terminology was used in most studies, referring to the pathophysiological process of deafferentiation between the cochlear nerve fibers and inner hair cells.
Topics: Humans; Hearing Loss, Noise-Induced; Auditory Threshold; Evoked Potentials, Auditory, Brain Stem; Cochlea; Noise; Deafness
PubMed: 37991055
DOI: 10.1590/2317-1782/20232023032pt -
Journal of Veterinary Diagnostic... Nov 2023An 11-y-old hembra alpaca was admitted because of cerebellar and vestibular signs, dysphagia, and aspiration pneumonia; without clinical improvement following empirical...
An 11-y-old hembra alpaca was admitted because of cerebellar and vestibular signs, dysphagia, and aspiration pneumonia; without clinical improvement following empirical therapy, the patient was euthanized. On autopsy, a neoplasm was found incorporating the right vestibulocochlear nerve at the level of the acoustic meatus. Histologically, the mass was composed of a multiphasic primitive cell population associated with a dense fibrous stroma and enveloping a remnant ganglion and nerve bundles. Patterns included dense ribbons and cords of embryonal neuroepithelial cells admixed with loosely defined interlacing spindle cells. The embryonal cells had angular cell profiles with variable amounts of lightly basophilic cytoplasm, ovoid-to-irregular nuclei, and an open chromatin pattern with a typically inapparent nucleolus. Necrosis was not evident, and there was 1 mitotic figure per 2.37 mm. The entire mass was infiltrated by small numbers of lymphocytes and plasma cells. Immunohistochemistry (IHC) revealed strong and diffuse cytoplasmic immunolabeling for vimentin, microtubule-associated protein-2, protein gene product 9.5, and synaptophysin; ~50% immunolabeling for cytokeratin AE1/3; sporadic OLIG2 and S100 immunolabeling; and absent glial fibrillary acidic protein immunolabeling. Based on the histologic pattern and the IHC results, our diagnosis was a poorly differentiated embryonal tumor with ependymal differentiation associated with the vestibulocochlear nerve.
Topics: Animals; Camelids, New World; Neoplasms, Germ Cell and Embryonal
PubMed: 37638696
DOI: 10.1177/10406387231195611 -
Journal of the Association For Research... Aug 2023Patients with bilateral vestibulopathy suffer from a variety of complaints, leading to a high individual and social burden. Available treatments aim to alleviate the... (Review)
Review
Patients with bilateral vestibulopathy suffer from a variety of complaints, leading to a high individual and social burden. Available treatments aim to alleviate the impact of this loss and improve compensatory strategies. Early experiments with electrical stimulation of the vestibular nerve in combination with knowledge gained by cochlear implant research, have inspired the development of a vestibular neuroprosthesis that can provide the missing vestibular input. The feasibility of this concept was first demonstrated in animals and later in humans. Currently, several research groups around the world are investigating prototype vestibular implants, in the form of vestibular implants as well as combined cochlear and vestibular implants. The aim of this review is to convey the presentations and discussions from the identically named symposium that was held during the 2021 MidWinter Meeting of the Association for Research in Otolaryngology, with researchers involved in the development of vestibular implants targeting the ampullary nerves. Substantial advancements in the development have been made. Yet, research and development processes face several challenges to improve this neuroprosthesis. These include, but are not limited to, optimization of the electrical stimulation profile, refining the surgical implantation procedure, preserving residual labyrinthine functions including hearing, as well as gaining regulatory approval and establishing a clinical care infrastructure similar to what exists for cochlear implants. It is believed by the authors that overcoming these challenges will accelerate the development and increase the impact of a clinically applicable vestibular implant.
Topics: Animals; Humans; Cochlear Implantation; Vestibule, Labyrinth; Cochlear Implants; Bilateral Vestibulopathy; Cochlea
PubMed: 37516679
DOI: 10.1007/s10162-023-00906-1