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Development (Cambridge, England) Jun 2020The cochlea, a coiled structure located in the ventral region of the inner ear, acts as the primary structure for the perception of sound. Along the length of the... (Review)
Review
The cochlea, a coiled structure located in the ventral region of the inner ear, acts as the primary structure for the perception of sound. Along the length of the cochlear spiral is the organ of Corti, a highly derived and rigorously patterned sensory epithelium that acts to convert auditory stimuli into neural impulses. The development of the organ of Corti requires a series of inductive events that specify unique cellular characteristics and axial identities along its three major axes. Here, we review recent studies of the cellular and molecular processes regulating several aspects of cochlear development, such as axial patterning, cochlear outgrowth and cellular differentiation. We highlight how the precise coordination of multiple signaling pathways is required for the successful formation of a complete organ of Corti.
Topics: Animals; Auditory Perception; Cell Differentiation; Cochlea; Hair Cells, Auditory; Mitosis; Organ of Corti; SOXB1 Transcription Factors; Signal Transduction
PubMed: 32571852
DOI: 10.1242/dev.162263 -
Trends in Neurosciences Jun 2019Sensory hair cells of the inner ear are exposed to continuous mechanical stress, causing damage over time. The maintenance of hair cells is further challenged by damage... (Review)
Review
Sensory hair cells of the inner ear are exposed to continuous mechanical stress, causing damage over time. The maintenance of hair cells is further challenged by damage from a variety of other ototoxic factors, including loud noise, aging, genetic defects, and ototoxic drugs. This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to loss of specialized ribbon synapses, and may even result in hair cell death. Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Here, we discuss how several key hair cell structures can be damaged, and what is known about how they are repaired.
Topics: Animals; Hair Cells, Auditory, Inner; Humans
PubMed: 30992136
DOI: 10.1016/j.tins.2019.03.006 -
Biomedicine & Pharmacotherapy =... Jan 2023Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis... (Review)
Review
Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis injury, spiral ganglion degeneration, and hair cell death. Over several decades, the research scope of cisplatin-induced ototoxicity has expanded with the discovery of the molecular mechanism mediating inner ear cell death, highlighting the roles of reactive oxygen species and transport channels for cisplatin uptake into inner ear cells. Upon entering hair cells, cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause intracellular damage. Recent studies have also reported the role of inflammation in cisplatin-induced ototoxicity. In this article, we preform a narrative review of the latest reported molecular mechanisms of cisplatin-induced ototoxicity, from extracellular to intracellular. We build up a signaling network starting with cisplatin entering into the inner ear through the blood labyrinth barrier, disrupting cochlear endolymph homeostasis, and activating inflammatory responses of the outer hair cells. After entering the hair cells, cisplatin causes hair cell death via DNA damage, redox system imbalance, and mitochondrial and endoplasmic reticulum dysfunction, culminating in programmed cell death including apoptosis, necroptosis, autophagic death, pyroptosis, and ferroptosis. Based on the mentioned mechanisms, prominent therapeutic targets, such as channel-blocking drugs of cisplatin transporter, construction of cisplatin structural analogues, anti-inflammatory drugs, antioxidants, cell death inhibitors, and others, were collated. Considering the recent research efforts, we have analyzed the feasibility of the aforementioned therapeutic strategies and proposed our otoprotective approaches to overcome cisplatin-induced ototoxicity.
Topics: Humans; Cisplatin; Antineoplastic Agents; Hair Cells, Auditory; Ototoxicity; Cochlea; Apoptosis
PubMed: 36455457
DOI: 10.1016/j.biopha.2022.114045 -
Cell Reports Sep 2021Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of...
Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.
Topics: Animals; Cochlea; Ear, Inner; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Mice; Neurons; Noise; Spiral Ganglion
PubMed: 34592158
DOI: 10.1016/j.celrep.2021.109758 -
International Journal of Molecular... Oct 2022RNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein... (Review)
Review
RNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein isoforms as well as in the maintenance of protein homeostasis. The inner ear is a bi-functional organ, with the cochlea and the vestibular system required for hearing and for maintaining balance, respectively. It is relatively well documented that transcription factors and signaling pathways are critically involved in the formation of inner ear structures and in the development of hair cells. Accumulating evidence highlights emerging functions of RBPs in the post-transcriptional regulation of inner ear development and hair cell function. Importantly, mutations of splicing factors of the RBP family and defective alternative splicing, which result in inappropriate expression of protein isoforms, lead to deafness in both animal models and humans. Because RBPs are critical regulators of cell proliferation and differentiation, they present the potential to promote hair cell regeneration following noise- or ototoxin-induced damage through mitotic and non-mitotic mechanisms. Therefore, deciphering RBP-regulated events during inner ear development and hair cell regeneration can help define therapeutic strategies for treatment of hearing loss. In this review, we outline our evolving understanding of the implications of RBPs in hair cell formation and hearing disease with the aim of promoting future research in this field.
Topics: Animals; Humans; Ear, Inner; Transcription Factors; RNA-Binding Proteins; RNA Splicing Factors; Hair
PubMed: 36293251
DOI: 10.3390/ijms232012393 -
Cold Spring Harbor Perspectives in... Sep 2019Over 450 million people worldwide suffer from hearing loss, leading to an estimated economic burden of ∼$750 billion. The past decade has seen significant advances in... (Review)
Review
Over 450 million people worldwide suffer from hearing loss, leading to an estimated economic burden of ∼$750 billion. The past decade has seen significant advances in the understanding of the molecular mechanisms that contribute to hearing, and the environmental and genetic factors that can go awry and lead to hearing loss. This in turn has sparked enormous interest in developing gene therapy approaches to treat this disorder. This review documents the most recent advances in cochlear gene therapy to restore hearing loss, and will cover viral vectors and construct designs, potential routes of delivery into the inner ear, and, lastly, the most promising genes of interest.
Topics: Animals; Cochlea; Genetic Therapy; Genetic Vectors; Hearing Loss; Humans
PubMed: 30323014
DOI: 10.1101/cshperspect.a033191 -
Cell Reports Jun 2023Inner ear disorders are among the most common congenital abnormalities; however, current tissue culture models lack the cell type diversity to study these disorders and...
Inner ear disorders are among the most common congenital abnormalities; however, current tissue culture models lack the cell type diversity to study these disorders and normal otic development. Here, we demonstrate the robustness of human pluripotent stem cell-derived inner ear organoids (IEOs) and evaluate cell type heterogeneity by single-cell transcriptomics. To validate our findings, we construct a single-cell atlas of human fetal and adult inner ear tissue. Our study identifies various cell types in the IEOs including periotic mesenchyme, type I and type II vestibular hair cells, and developing vestibular and cochlear epithelium. Many genes linked to congenital inner ear dysfunction are confirmed to be expressed in these cell types. Additional cell-cell communication analysis within IEOs and fetal tissue highlights the role of endothelial cells on the developing sensory epithelium. These findings provide insights into this organoid model and its potential applications in studying inner ear development and disorders.
Topics: Humans; Endothelial Cells; Cochlea; Vestibule, Labyrinth; Epithelium; Organoids
PubMed: 37289589
DOI: 10.1016/j.celrep.2023.112623 -
Proceedings of the National Academy of... Apr 2023Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing...
Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of and reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the nontransgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD "rejuvenates" the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite / activation. We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of and We show that the cocktail effectively replaces and transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.
Topics: Mice; Animals; Cell Proliferation; Hair Cells, Auditory; Ear, Inner; Cochlea; Regeneration; Mammals
PubMed: 37068229
DOI: 10.1073/pnas.2215253120 -
Genes May 2022The inner ear is a complex structure at the cellular and molecular levels [...].
The inner ear is a complex structure at the cellular and molecular levels [...].
Topics: Ear, Inner; Hearing Loss; Humans
PubMed: 35627237
DOI: 10.3390/genes13050852