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In Vivo (Athens, Greece) 2021Hearing loss is one of the major worldwide health problems that seriously affects human social and cognitive development. In the auditory system, three components outer... (Review)
Review
Hearing loss is one of the major worldwide health problems that seriously affects human social and cognitive development. In the auditory system, three components outer ear, middle ear and inner ear are essential for the hearing mechanism. In the inner ear, sensory hair cells and ganglion neuronal cells are the essential supporters for hearing mechanism. Damage to these cells can be caused by long-term exposure of excessive noise, ototoxic drugs (aminoglycosides), ear tumors, infections, heredity and aging. Since mammalian cochlear hair cells do not regenerate naturally, some therapeutic interventions may be required to replace the damaged or lost cells. Cochlear implants and hearing aids are the temporary solutions for people suffering from severe hearing loss. The current discoveries in gene therapy may provide a deeper understanding in essential genes for the inner ear regeneration. Stem cell migration, survival and differentiation to supporting cells, cochlear hair cells and spiral ganglion neurons are the important foundation in understanding stem cell therapy. Moreover, mesenchymal stem cells (MSCs) from different sources (bone marrow, umbilical cord, adipose tissue and placenta) could be used in inner ear therapy. Transplanted MSCs in the inner ear can recruit homing factors at the damaged sites to induce transdifferentiation into inner hair cells and ganglion neurons or regeneration of sensory hair cells, thus enhancing the cochlear function. This review summarizes the potential application of mesenchymal stem cells in hearing restoration and combining stem cell and molecular therapeutic strategies can also be used in the recovery of cochlear function.
Topics: Animals; Ear, Inner; Hair Cells, Auditory, Inner; Humans; Mesenchymal Stem Cells; Spiral Ganglion; Stem Cell Transplantation
PubMed: 33402445
DOI: 10.21873/invivo.12227 -
LDL receptor-related protein 1 (LRP1), a novel target for opening the blood-labyrinth barrier (BLB).Signal Transduction and Targeted Therapy Jun 2022Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier...
Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.
Topics: Drug Delivery Systems; Ear, Inner; Hearing Loss; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Pharmaceutical Preparations
PubMed: 35680846
DOI: 10.1038/s41392-022-00995-z -
The International Journal of... 2017The inner ear is composed of a complex mixture of cells, which together allow organisms to hear and maintain balance. The cells in the inner ear, which undergo an... (Review)
Review
The inner ear is composed of a complex mixture of cells, which together allow organisms to hear and maintain balance. The cells in the inner ear, which undergo an extraordinary process of development, have only recently begun to be studied on an individual level. As it has recently become clear that individual cells, previously considered to be of uniform character, may differ dramatically from each other, the need to study cell-to-cell variation, along with distinct transcriptional and regulatory signatures, has taken hold in the scientific community. In conjunction with high-throughput technologies, attempts are underway to dissect the inter- and intra-cellular variability of different cell types and developmental states of the inner ear from a novel perspective. Single cell analysis of the inner ear sensory organs holds the promise of providing a significant boost in building an omics network that translates into a comprehensive understanding of the mechanisms of hearing and balance. These networks may uncover critical elements for trans-differentiation, regeneration and/or reprogramming, providing entry points for therapeutics of deafness and vestibular pathologies.
Topics: Animals; Cell Differentiation; Ear, Inner; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genome; Humans; Microscopy, Fluorescence; Regeneration; Signal Transduction; Single-Cell Analysis; Stem Cells; Transcription, Genetic; Transcriptome
PubMed: 28621418
DOI: 10.1387/ijdb.160453ka -
Hearing Research Oct 2018Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we... (Review)
Review
Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration.
Topics: Animals; Drug Delivery Systems; Ear, Inner; Hearing; Hearing Loss; Humans; Labyrinth Diseases; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 29551306
DOI: 10.1016/j.heares.2018.03.002 -
AJNR. American Journal of Neuroradiology Apr 2009Complete labyrinthine aplasia (CLA), also referred to as Michel aplasia, is a severe congenital anomaly of the inner ear, defined by the complete absence of inner ear... (Review)
Review
BACKGROUND AND PURPOSE
Complete labyrinthine aplasia (CLA), also referred to as Michel aplasia, is a severe congenital anomaly of the inner ear, defined by the complete absence of inner ear structures. The purpose of this study was to document the imaging findings in a series of patients with CLA, with review of the literature, to better understand this anomaly.
MATERIALS AND METHODS
The CT and MR imaging findings of 9 patients (14 ears with CLA) were retrospectively evaluated. The audiologic tests and patient charts were also retrospectively reviewed.
RESULTS
CLA was bilateral in 5 and unilateral in 4 patients. The petrous bone was hypoplastic in all 14 ears, but the otic capsule was aplastic in only 5. The middle ear and mastoid volumes were decreased in most of the ears. The stapes was aplastic in 1 ear and was dysplastic in 5 ears. The internal acoustic canal was aplastic in 4 ears and markedly narrowed in 10 ears. The facial nerve canal showed a variety of anomalies and aberrant courses in 11/14 ears. The bony covering of the jugular bulb was defective in 9 ears. Tegmen tympani defects were seen in 3 patients, and there were several accompanying skull base and posterior fossa anomalies.
CONCLUSIONS
Although CLA is a rare developmental anomaly, its accurate diagnosis and its differential diagnosis from labyrinthine ossificans is crucial. Proper guidance of these patients for brain stem implantation in the critical period of brain development depends on the recognition of the characteristic imaging findings of CLA.
Topics: Adolescent; Audiology; Child; Child, Preschool; Ear, Inner; Female; Humans; Labyrinth Diseases; Magnetic Resonance Imaging; Male; Retrospective Studies; Tomography, X-Ray Computed
PubMed: 19147720
DOI: 10.3174/ajnr.A1426 -
The FEBS Journal Dec 2022The inner ear is a complex organ that encodes sound, motion, and orientation in space. Given the complexity of the inner ear, it is not surprising that treatments are... (Review)
Review
The inner ear is a complex organ that encodes sound, motion, and orientation in space. Given the complexity of the inner ear, it is not surprising that treatments are relatively limited despite the fact that, in 2015, hearing loss was the fourth leading cause of years lived with disability worldwide. Inner ear organoid models are a promising tool to advance the study of multiple aspects of the inner ear to aid the development of new treatments and validate drug-based therapies. The blood supply of the inner ear plays a pivotal role in growth, maturation, and survival of inner ear tissues and their physiological functions. This vasculature cannot be ignored in order to achieve a truly in vivo-like model that mimics the microenvironment and niches of organ development. However, this aspect of organoid development has remained largely absent in the generation of inner ear organoids. The current review focuses on three-dimensional inner ear organoid and how recent technical progress in generating in vitro vasculature can enhance the next generation of these models.
Topics: Ear, Inner
PubMed: 34331740
DOI: 10.1111/febs.16146 -
BMC Cell Biology May 2016Pannexin (Panx) is a gene family encoding gap junction proteins in vertebrates. So far, three isoforms (Panx1, 2 and 3) have been identified. All of three Panx isoforms... (Review)
Review
Pannexin (Panx) is a gene family encoding gap junction proteins in vertebrates. So far, three isoforms (Panx1, 2 and 3) have been identified. All of three Panx isoforms express in the cochlea with distinct expression patterns. Panx1 expresses in the cochlea extensively, including the spiral limbus, the organ of Corti, and the cochlear lateral wall, whereas Panx2 and Panx3 restrict to the basal cells of the stria vascularis in the lateral wall and the cochlear bony structure, respectively. However, there is no pannexin expression in auditory sensory hair cells. Recent studies demonstrated that like connexin gap junction gene, Panx1 deficiency causes hearing loss. Panx1 channels dominate ATP release in the cochlea. Deletion of Panx1 abolishes ATP release in the cochlea and reduces endocochlear potential (EP), auditory receptor current/potential, and active cochlear amplification. Panx1 deficiency in the cochlea also activates caspase-3 cell apoptotic pathway leading to cell degeneration. These new findings suggest that pannexins have a critical role in the cochlea in regard to hearing. However, detailed information about pannexin function in the cochlea and Panx mutation induced hearing loss still remain largely undetermined. Further studies are required.
Topics: Animals; Cochlea; Deafness; Ear, Inner; Hearing; Humans; Nerve Tissue Proteins
PubMed: 27229462
DOI: 10.1186/s12860-016-0095-7 -
Development (Cambridge, England) Jun 2023The inner ear sensory epithelia contain mechanosensitive hair cells and supporting cells. Both cell types arise from SOX2-expressing prosensory cells, but the mechanisms...
The inner ear sensory epithelia contain mechanosensitive hair cells and supporting cells. Both cell types arise from SOX2-expressing prosensory cells, but the mechanisms underlying the diversification of these cell lineages remain unclear. To determine the transcriptional trajectory of prosensory cells, we established a SOX2-2A-ntdTomato human embryonic stem cell line using CRISPR/Cas9, and performed single-cell RNA-sequencing analyses with SOX2-positive cells isolated from inner ear organoids at various time points between differentiation days 20 and 60. Our pseudotime analysis suggests that vestibular type II hair cells arise primarily from supporting cells, rather than bi-fated prosensory cells in organoids. Moreover, ion channel- and ion-transporter-related gene sets were enriched in supporting cells versus prosensory cells, whereas Wnt signaling-related gene sets were enriched in hair cells versus supporting cells. These findings provide valuable insights into how prosensory cells give rise to hair cells and supporting cells during human inner ear development, and may provide a clue to promote hair cell regeneration from resident supporting cells in individuals with hearing loss or balance disorders.
Topics: Humans; Organoids; Hair Cells, Auditory; Hair Cells, Vestibular; Vestibule, Labyrinth; Cell Differentiation
PubMed: 37381908
DOI: 10.1242/dev.201071 -
Biomolecules Mar 2022Cochlear implantation initiates an inflammatory cascade in which both acute insertion trauma and chronic foreign body reaction lead to intracochlear fibrosis and loss of... (Review)
Review
Cochlear implantation initiates an inflammatory cascade in which both acute insertion trauma and chronic foreign body reaction lead to intracochlear fibrosis and loss of residual hearing. Several strategies have been proposed to attenuate the local reactive process after implantation, including intracochlear drug delivery. The present study gives an overview of what is being investigated in the field of inner ear therapeutics and cochlear implant surgery. The aim is to evaluate its potential benefit in clinical practice. A systematic search was conducted in PubMed, Embase, and Cochrane Library databases identifying comparative prospective studies examining the effect of direct inner ear drug application on mechanical cochlear trauma. Both animal and human studies were considered and all studies were assessed for quality according to the validated risk of bias tools. Intracochlear administration of drugs is a feasible method to reduce the local inflammatory reaction following cochlear implantation. In animal studies, corticosteroid use had a significant effect on outcome measures including auditory brainstem response, impedance, and histological changes. This effect was, however, only durable with prolonged drug delivery. Significant differences in outcome were predominantly seen in studies where the cochlear damage was extensive. Six additional reports assessing non-steroidal agents were found. Overall, evidence of anti-inflammatory effects in humans is still scarce.
Topics: Animals; Cochlear Implantation; Cochlear Implants; Ear, Inner; Hearing; Prospective Studies
PubMed: 35454118
DOI: 10.3390/biom12040529 -
Genes Nov 2020The etiology of hearing impairment following cochlear damage can be caused by many factors, including congenital or acquired onset, ototoxic drugs, noise exposure, and... (Review)
Review
The etiology of hearing impairment following cochlear damage can be caused by many factors, including congenital or acquired onset, ototoxic drugs, noise exposure, and aging. Regardless of the many different etiologies, a common pathologic change is auditory cell death. It may be difficult to explain hearing impairment only from the aspect of cell death including apoptosis, necrosis, or necroptosis because the level of hearing loss varies widely. Therefore, we focused on autophagy as an intracellular phenomenon functionally competing with cell death. Autophagy is a dynamic lysosomal degradation and recycling system in the eukaryotic cell, mandatory for controlling the balance between cell survival and cell death induced by cellular stress, and maintaining homeostasis of postmitotic cells, including hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear. Autophagy is considered a candidate for the auditory cell fate decision factor, whereas autophagy deficiency could be one of major causes of hearing impairment. In this paper, we review the molecular mechanisms and biologic functions of autophagy in the auditory system and discuss the latest research concerning autophagy-related genes and sensorineural hearing loss to gain insight into the role of autophagic mechanisms in inner-ear disorders.
Topics: Apoptosis; Autophagy; Cell Death; Ear, Inner; Hair Cells, Auditory; Hearing; Hearing Loss; Humans; Neurons; Spiral Ganglion
PubMed: 33187328
DOI: 10.3390/genes11111331