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Aghajanloo B, Nazarnezhad S, Arshadi F, Prakash Kottapalli AG, Pastras C, Asadnia M. Emerging trends in biosensor and microfluidics integration for inner ear theragnostics. Biosens Bioelectron 2025; 286:117588. [PMID: 40408897 DOI: 10.1016/j.bios.2025.117588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/31/2025] [Accepted: 05/14/2025] [Indexed: 05/25/2025]
Abstract
Advancements in inner ear theragnostics are critical for addressing the pervasive challenges of diagnosing and treating hearing and balance disorders, which significantly impact quality of life. This paper reviews biosensors and devices that leverage advanced functional nanomaterials, microfabrication techniques, and nano-biotechnology to enhance theragnostic applications for the inner ear. The paper highlights the development of diverse electromechanical, electrochemical, and biomarker sensors for inner ear theragnostics. Electromechanical sensors replicate the cochlear and vestibular sensory structures through bioinspired designs, while electrochemical sensors are used to measure the level of ions and chemicals in the inner ear fluid, providing insights into the health and disease of the hearing and balance organs. Biomarker sensors focus on screening of inner ear diseases through early detection of correlated biomarkers based on point of care diagnostics. This study also examines the use of microfluidic devices with sensory elements to provide a compact and integrated model of the fluid-filled cochlea. In addition, advanced delivery strategies, including targeted drug delivery systems and nanocarriers are explored for their ability to improve the penetration and distribution of therapeutics within the inner ear. The study also highlights the importance of pharmacokinetics and post-treatment monitoring as critical indicators for assessing the efficacy of micro/nanotechnology-based theragnostic approaches. By consolidating these innovations, this work offers a comprehensive framework for advancing otology, paving the way for novel diagnostic tools, effective treatments, and future clinical applications.
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Affiliation(s)
| | - Simin Nazarnezhad
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Arshadi
- School of Engineering, Macquarie University, Sydney, Australia
| | - Ajay Giri Prakash Kottapalli
- Department of Bioinspired MEMS and Biomedical Devices (BMBD), Engineering and Technology Institute (ENTEG), University of Groningen, Groningen, Netherlands
| | | | - Mohsen Asadnia
- School of Engineering, Macquarie University, Sydney, Australia.
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Zhang J, Gong T, Chen P, Zhu J, Huang S, Li Y, Li G, Zhang Q, Duan M, Song Q, Yang J, Hou S. Connexin30-deficient mice increase susceptibility to noise via redox and lactate imbalances. Free Radic Biol Med 2024; 225:641-653. [PMID: 39396580 DOI: 10.1016/j.freeradbiomed.2024.10.280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 09/03/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
Noise significantly contributes to one-third of the global burden of hearing loss. The intricate interplay of genetic and environmental factors impacts various molecular and cellular processes that lead to noise-induced hearing loss (NIHL). Defective connexin 26 (Cx26) and connexin 30 (Cx30), encoded by Gjb2/Cx26 and Gjb6/Cx30, respectively, are prevalent causes of hereditary deafness. However, the role of Cx30 in the pathogenesis of NIHL remains unclear. Herein, we observed that homozygous Cx30 knockout (Cx30 KO) mice exhibited poorer hearing recovery after noise exposure (97 dB mean sound pressure level for 2 h) and increased susceptibility to noise. In addition to the exacerbation of noise-induced damage to hair cells and synapses, Cx30 KO mice exposed to noise exhibited increased oxidative stress. The 2-(N-(7-nitrobenz-2-oxa-1,3-dia-zol-4-yl) amino)-2-deoxyglucose assay showed a reduction in glucose levels associated with a decrease in gap junctions as well as a reduction in adenosine triphosphate release. Glucose metabolomics analysis further revealed that Cx30 KO mice had elevated lactate and NAD + levels after noise exposure, thus worsening anaerobic oxidation from glycolysis. Our study emphasizes that Cx30-deficient mice increase susceptibility to noise via redox and lactate imbalances in the cochlea.
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Affiliation(s)
- Jifang Zhang
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Tianyu Gong
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Penghui Chen
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Jingyi Zhu
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Sihan Huang
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Yue Li
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Guiping Li
- Shanghai Jiaotong University School of Medicine, China
| | - Qing Zhang
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China
| | - Maoli Duan
- Ear Nose and Throat Patient Area, Trauma and Reparative Medicine Theme, Karolinska University Hospital, Stockholm, Sweden; Division of Ear, Nose and Throat Diseases, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Qiang Song
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China.
| | - Jun Yang
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China.
| | - Shule Hou
- Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China.
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Cai W, Huang Z, Sun B, Lu L, Ding X, Tao F. The differentiation of Lgr5+ progenitor cells on nanostructures of self-assembled silica beads. PLoS One 2024; 19:e0304809. [PMID: 38995923 PMCID: PMC11244819 DOI: 10.1371/journal.pone.0304809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 05/19/2024] [Indexed: 07/14/2024] Open
Abstract
Supporting cells(SCs) have been demonstrated to be a reliable source for regenerating hair cells(HCs). Previous research has reported that Lgr5+ SCs can regenerate HCs both in vitro and in vivo. However, there is limited knowledge about the impact of the material on Lgr5+ cells. In this study, Lgr5+ cells were isolated from neonatal Lgr5-EGFP-CreERT2 transgenic mice by flow cytometry and then plated on self-assembled silica beads (SB). Lgr5+ cell differentiation was observed by immunofluorescence. We found that in the direct differentiation assay, the SB group generated more hair cells than the control group(*p < 0.05). Especially in the SB group, Lgr5+ progenitors generated significantly more Myo7a+ HCs outside of the colony than in the control group(**p < 0.01). In the sphere differentiation assay, we found that the diameter of spheres in the SB group was significantly larger compared to those of the control group(**p < 0.01). However, the difference in the ratio of myo7a+ cell counts was not obvious(P>0.05). The experiment proved that the self-assembled silica beads could promote the differentiation of Lgr5+ progenitors in vitro. Our findings implicate that nanostructures of self-assembled silica beads can be used as vectors for stem cell research in the inner ear.
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Affiliation(s)
- Wenjun Cai
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhong Da Hospital, Southeast University, Nanjing, China
| | - Zhichun Huang
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhong Da Hospital, Southeast University, Nanjing, China
| | - Baobin Sun
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhong Da Hospital, Southeast University, Nanjing, China
| | - Ling Lu
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhong Da Hospital, Southeast University, Nanjing, China
| | - Xiaoqiong Ding
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhong Da Hospital, Southeast University, Nanjing, China
| | - Feng Tao
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhong Da Hospital, Southeast University, Nanjing, China
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Lipovsek M. Comparative biology of the amniote vestibular utricle. Hear Res 2024; 448:109035. [PMID: 38763033 DOI: 10.1016/j.heares.2024.109035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/21/2024]
Abstract
The sensory epithelia of the auditory and vestibular systems of vertebrates have shared developmental and evolutionary histories. However, while the auditory epithelia show great variation across vertebrates, the vestibular sensory epithelia appear seemingly more conserved. An exploration of the current knowledge of the comparative biology of the amniote utricle, a vestibular sensory epithelium that senses linear acceleration, shows interesting instances of variability between birds and mammals. The distribution of sensory hair cell types, the position of the line of hair bundle polarity reversal and the properties of supporting cells show marked differences, likely impacting vestibular function and hair cell regeneration potential.
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Affiliation(s)
- Marcela Lipovsek
- Ear Institute, Faculty of Brain Sciences, University College London, London, UK.
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Sato MP, Benkafadar N, Heller S. Hair cell regeneration, reinnervation, and restoration of hearing thresholds in the avian hearing organ. Cell Rep 2024; 43:113822. [PMID: 38393948 PMCID: PMC11068303 DOI: 10.1016/j.celrep.2024.113822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 12/13/2023] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Hearing starts, at the cellular level, with mechanoelectrical transduction by sensory hair cells. Sound information is then transmitted via afferent synaptic connections with auditory neurons. Frequency information is encoded by the location of hair cells along the cochlear duct. Loss of hair cells, synapses, or auditory neurons leads to permanent hearing loss in mammals. Birds, in contrast, regenerate auditory hair cells and functionally recover from hearing loss. Here, we characterized regeneration and reinnervation in sisomicin-deafened chickens and found that afferent neurons contact regenerated hair cells at the tips of basal projections. In contrast to development, synaptic specializations are established at these locations distant from the hair cells' bodies. The protrusions then contracted as regenerated hair cells matured and became functional 2 weeks post-deafening. We found that auditory thresholds recovered after 4-5 weeks. We interpret the regeneration-specific synaptic reestablishment as a location-preserving process that might be needed to maintain tonotopic fidelity.
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Affiliation(s)
- Mitsuo P Sato
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Otolaryngology-Head and Neck Surgery, Kindai University School of Medicine, Osaka, Japan
| | - Nesrine Benkafadar
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Stefan Heller
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Lu PH, Ma PW, Wang WL, Gao W, Chen JW, Yuan H, Ding XR, Lun YQ, Liang R, Li SY, Wang Z, Guo JN, Mei HK, Lu LJ. Deferoxamine protects cochlear hair cells and hair cell-like HEI-OC1 cells against tert-butyl hydroperoxide-induced ototoxicity. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167024. [PMID: 38242180 DOI: 10.1016/j.bbadis.2024.167024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/30/2023] [Accepted: 01/08/2024] [Indexed: 01/21/2024]
Abstract
Oxidative stress is the common mechanism of sensorineural hearing loss (SNHL) caused by many factors, such as noise, drugs and ageing. Here, we used tert-butyl hydroperoxide (t-BHP) to cause oxidative stress damage in HEI-OC1 cells and in an in vitro cochlear explant model. We observed lipid peroxidation, iron accumulation, mitochondrial shrinkage and vanishing of mitochondrial cristae, which caused hair cell ferroptosis, after t-BHP exposure. Moreover, the number of TUNEL-positive cells in cochlear explants and HEI-OC1 cells increased significantly, suggesting that t-BHP caused the apoptosis of hair cells. Administration of deferoxamine (DFOM) significantly attenuated t-BHP-induced hair cell loss and disordered hair cell arrangement in cochlear explants as well as HEI-OC1 cell death, including via apoptosis and ferroptosis. Mechanistically, we found that DFOM treatment reduced t-BHP-induced lipid peroxidation, iron accumulation and mitochondrial pathological changes in hair cells, consequently mitigating apoptosis and ferroptosis. Moreover, DFOM treatment alleviated GSH depletion caused by t-BHP and activated the Nrf2 signalling pathway to exert a protective effect. Furthermore, we confirmed that the protective effect of DFOM mainly depended on its ability to chelate iron by constructing Fth1 knockout (KO), TfR1 KO and Nrf2 KO HEI-OC1 cell lines using CRISPR/Cas9 technology and a Flag-Fth1 (overexpression) HEI-OC1 cell line using the FlpIn™ System. Our findings suggest that DFOM is a potential drug for SNHL treatment due to its ability to inhibit apoptosis and ferroptosis by chelating iron and scavenging reactive oxygen species (ROS).
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Affiliation(s)
- Pei-Heng Lu
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Peng-Wei Ma
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Wei-Long Wang
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Wei Gao
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jia-Wei Chen
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Hao Yuan
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Xue-Rui Ding
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Yu-Qiang Lun
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Rui Liang
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Si-Yu Li
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Zi Wang
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jia-Ning Guo
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Hong-Kai Mei
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Lian-Jun Lu
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China.
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Pan X, Li Y, Huang P, Staecker H, He M. Extracellular vesicles for developing targeted hearing loss therapy. J Control Release 2024; 366:460-478. [PMID: 38182057 DOI: 10.1016/j.jconrel.2023.12.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/19/2023] [Accepted: 12/28/2023] [Indexed: 01/07/2024]
Abstract
Substantial efforts have been made for local administration of small molecules or biologics in treating hearing loss diseases caused by either trauma, genetic mutations, or drug ototoxicity. Recently, extracellular vesicles (EVs) naturally secreted from cells have drawn increasing attention on attenuating hearing impairment from both preclinical studies and clinical studies. Highly emerging field utilizing diverse bioengineering technologies for developing EVs as the bioderived therapeutic materials, along with artificial intelligence (AI)-based targeting toolkits, shed the light on the unique properties of EVs specific to inner ear delivery. This review will illuminate such exciting research field from fundamentals of hearing protective functions of EVs to biotechnology advancement and potential clinical translation of functionalized EVs. Specifically, the advancements in assessing targeting ligands using AI algorithms are systematically discussed. The overall translational potential of EVs is reviewed in the context of auditory sensing system for developing next generation gene therapy.
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Affiliation(s)
- Xiaoshu Pan
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Yanjun Li
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, Florida 32610, United States
| | - Peixin Huang
- Department of Otolaryngology, Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas 66160, United States
| | - Hinrich Staecker
- Department of Otolaryngology, Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas 66160, United States.
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
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Choi SW, Abitbol JM, Cheng AG. Hair Cell Regeneration: From Animals to Humans. Clin Exp Otorhinolaryngol 2024; 17:1-14. [PMID: 38271988 PMCID: PMC10933805 DOI: 10.21053/ceo.2023.01382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 01/07/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
Cochlear hair cells convert sound into electrical signals that are relayed via the spiral ganglion neurons to the central auditory pathway. Hair cells are vulnerable to damage caused by excessive noise, aging, and ototoxic agents. Non-mammals can regenerate lost hair cells by mitotic regeneration and direct transdifferentiation of surrounding supporting cells. However, in mature mammals, damaged hair cells are not replaced, resulting in permanent hearing loss. Recent studies have uncovered mechanisms by which sensory organs in non-mammals and the neonatal mammalian cochlea regenerate hair cells, and outlined possible mechanisms why this ability declines rapidly with age in mammals. Here, we review similarities and differences between avian, zebrafish, and mammalian hair cell regeneration. Moreover, we discuss advances and limitations of hair cell regeneration in the mature cochlea and their potential applications to human hearing loss.
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Affiliation(s)
- Sung-Won Choi
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Department of Otorhinolaryngology-Head and Neck Surgery and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University School of Medicine, Busan, Korea
| | - Julia M. Abitbol
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Alan G. Cheng
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
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Abstract
Permanent fibrosis and chronic deterioration of heart function in patients after myocardial infarction present a major health-care burden worldwide. In contrast to the restricted potential for cellular and functional regeneration of the adult mammalian heart, a robust capacity for cardiac regeneration is seen during the neonatal period in mammals as well as in the adults of many fish and amphibian species. However, we lack a complete understanding as to why cardiac regeneration takes place more efficiently in some species than in others. The capacity of the heart to regenerate after injury is controlled by a complex network of cellular and molecular mechanisms that form a regulatory landscape, either permitting or restricting regeneration. In this Review, we provide an overview of the diverse array of vertebrates that have been studied for their cardiac regenerative potential and discuss differential heart regeneration outcomes in closely related species. Additionally, we summarize current knowledge about the core mechanisms that regulate cardiac regeneration across vertebrate species.
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Affiliation(s)
- Michael Weinberger
- Institute of Developmental & Regenerative Medicine, University of Oxford, Oxford, UK
- MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Paul R Riley
- Institute of Developmental & Regenerative Medicine, University of Oxford, Oxford, UK.
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Griffin C, Saint-Jeannet JP. In vitro modeling of cranial placode differentiation: Recent advances, challenges, and perspectives. Dev Biol 2024; 506:20-30. [PMID: 38052294 PMCID: PMC10843546 DOI: 10.1016/j.ydbio.2023.11.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 12/07/2023]
Abstract
Cranial placodes are transient ectodermal thickenings that contribute to a diverse array of organs in the vertebrate head. They develop from a common territory, the pre-placodal region that over time segregates along the antero-posterior axis into individual placodal domains: the adenohypophyseal, olfactory, lens, trigeminal, otic, and epibranchial placodes. These placodes terminally differentiate into the anterior pituitary, the lens, and contribute to sensory organs including the olfactory epithelium, and inner ear, as well as several cranial ganglia. To study cranial placodes and their derivatives and generate cells for therapeutic purposes, several groups have turned to in vitro derivation of placodal cells from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs). In this review, we summarize the signaling cues and mechanisms involved in cranial placode induction, specification, and differentiation in vivo, and discuss how this knowledge has informed protocols to derive cranial placodes in vitro. We also discuss the benefits and limitations of these protocols, and the potential of in vitro cranial placode modeling in regenerative medicine to treat cranial placode-related pathologies.
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Affiliation(s)
- Casey Griffin
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA
| | - Jean-Pierre Saint-Jeannet
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA.
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Jiang L, Wang D, He Y, Shu Y. Advances in gene therapy hold promise for treating hereditary hearing loss. Mol Ther 2023; 31:934-950. [PMID: 36755494 PMCID: PMC10124073 DOI: 10.1016/j.ymthe.2023.02.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/30/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing or reconstructing genetic material, thus being expected to be the most promising therapeutic strategy for genetic disorders. Due to the growing attention to hearing impairment, an increasing amount of research is attempting to utilize gene therapy for hereditary hearing loss (HHL), an important monogenic disease and the most common type of congenital deafness. Several gene therapy clinical trials for HHL have recently been approved, and, additionally, CRISPR-Cas tools have been attempted for HHL treatment. Therefore, in order to further advance the development of inner ear gene therapy and promote its broad application in other forms of genetic disease, it is imperative to review the progress of gene therapy for HHL. Herein, we address three main gene therapy strategies (gene replacement, gene suppression, and gene editing), summarizing the strategy that is most appropriate for particular monogenic diseases based on different pathogenic mechanisms, and then focusing on their successful applications for HHL in preclinical trials. Finally, we elaborate on the challenges and outlooks of gene therapy for HHL.
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Affiliation(s)
- Luoying Jiang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Daqi Wang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yingzi He
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.
| | - Yilai Shu
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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12
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Malfeld K, Armbrecht N, Pich A, Volk HA, Lenarz T, Scheper V. Prevention of Noise-Induced Hearing Loss In Vivo: Continuous Application of Insulin-like Growth Factor 1 and Its Effect on Inner Ear Synapses, Auditory Function and Perilymph Proteins. Int J Mol Sci 2022; 24:ijms24010291. [PMID: 36613734 PMCID: PMC9820558 DOI: 10.3390/ijms24010291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
As noise-induced hearing loss (NIHL) is a leading cause of occupational diseases, there is an urgent need for the development of preventive and therapeutic interventions. To avoid user-compliance-based problems occurring with conventional protection devices, the pharmacological prevention is currently in the focus of hearing research. Noise exposure leads to an increase in reactive oxygen species (ROS) in the cochlea. This way antioxidant agents are a promising option for pharmacological interventions. Previous animal studies reported preventive as well as therapeutic effects of Insulin-like growth factor 1 (IGF-1) in the context of NIHL. Unfortunately, in patients the time point of the noise trauma cannot always be predicted, and additive effects may occur. Therefore, continuous prevention seems to be beneficial. The present study aimed to investigate the preventive potential of continuous administration of low concentrations of IGF-1 to the inner ear in an animal model of NIHL. Guinea pigs were unilaterally implanted with an osmotic minipump. One week after surgery they received noise trauma, inducing a temporary threshold shift. Continuous IGF-1 delivery lasted for seven more days. It did not lead to significantly improved hearing thresholds compared to control animals. Quite the contrary, there is a hint for a higher noise susceptibility. Nevertheless, changes in the perilymph proteome indicate a reduced damage and better repair mechanisms through the IGF-1 treatment. Thus, future studies should investigate delivery methods enabling continuous prevention but reducing the risk of an overdosage.
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Affiliation(s)
- Kathrin Malfeld
- Department of Otolaryngology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany
| | - Nina Armbrecht
- Department of Otolaryngology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Andreas Pich
- Core Facility Proteomics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Holger A. Volk
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany
| | - Thomas Lenarz
- Department of Otolaryngology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Cluster of Excellence “Hearing4all”, German Research Foundation (DFG; “Deutsche Forschungsgemeinschaft”), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Verena Scheper
- Department of Otolaryngology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Cluster of Excellence “Hearing4all”, German Research Foundation (DFG; “Deutsche Forschungsgemeinschaft”), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Correspondence:
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13
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Ma PW, Wang WL, Chen JW, Yuan H, Lu PH, Gao W, Ding XR, Lun YQ, Liang R, He ZH, Yang Q, Lu LJ. Treatment with the Ferroptosis Inhibitor Ferrostatin-1 Attenuates Noise-Induced Hearing Loss by Suppressing Ferroptosis and Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3373828. [PMID: 36531206 PMCID: PMC9750774 DOI: 10.1155/2022/3373828] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/29/2022] [Accepted: 11/12/2022] [Indexed: 08/17/2023]
Abstract
Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise-induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin- and neomycin-induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer-1 on tert-butyl hydroperoxide (TBHP)-induced hair cell damage in vitro in cochlear explants and HEI-OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer-1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer-1 significantly alleviated noise-induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer-1 significantly reduced noise- and TBHP-induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer-1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer-1 exerted its protective effects by scavenging of ROS and inhibition of TfR1-mediated ferroptosis and P53-AIFM2 signaling pathway-mediated apoptosis. Our findings suggest that Fer-1 is a promising drug for treating NIHL because of its ability to inhibit noise-induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.
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Affiliation(s)
- Peng-Wei Ma
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Wei-Long Wang
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jia-Wei Chen
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Hao Yuan
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Pei-Heng Lu
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Wei Gao
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Xue-Rui Ding
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Yu-Qiang Lun
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Rui Liang
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Zu-Hong He
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qian Yang
- Department of Experimental Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Lian-Jun Lu
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
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14
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Pouyo R, Chung K, Delacroix L, Malgrange B. The ubiquitin-proteasome system in normal hearing and deafness. Hear Res 2022; 426:108366. [PMID: 34645583 DOI: 10.1016/j.heares.2021.108366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/03/2021] [Accepted: 09/23/2021] [Indexed: 12/16/2022]
Abstract
Post-translational modifications of proteins are essential for the proper development and function of many tissues and organs, including the inner ear. Ubiquitination is a highly selective post-translational modification that involves the covalent conjugation of ubiquitin to a substrate protein. The most common outcome of protein ubiquitination is degradation by the ubiquitin-proteasome system (UPS), preventing the accumulation of misfolded, damaged, and excess proteins. In addition to proteasomal degradation, ubiquitination regulates other cellular processes, such as transcription, translation, endocytosis, receptor activity, and subcellular localization. All of these processes are essential for cochlear development and maintenance, as several studies link impairment of UPS with altered cochlear development and hearing loss. In this review, we provide insight into the well-oiled machinery of UPS with a focus on its confirmed role in normal hearing and deafness and potential therapeutic strategies to prevent and treat UPS-associated hearing loss.
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Affiliation(s)
- Ronald Pouyo
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium
| | - Keshi Chung
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium
| | - Laurence Delacroix
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium
| | - Brigitte Malgrange
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium.
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15
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Liao M, Hu Y, Zhang Y, Wang K, Fang Q, Qi Y, Shen Y, Cheng H, Fu X, Tang M, Sun S, Gao X, Chai R. 3D Ti 3C 2T x MXene-Matrigel with Electroacoustic Stimulation to Promote the Growth of Spiral Ganglion Neurons. ACS NANO 2022; 16:16744-16756. [PMID: 36222600 PMCID: PMC9620407 DOI: 10.1021/acsnano.2c06306] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Cochlear implantation has become the most effective treatment method for patients with profound and total hearing loss. However, its therapeutic efficacy is dependent on the number and normal physiological function of cochlear implant-targeted spiral ganglion neurons (SGNs). Electrical stimulation can be used as an effective cue to regulate the morphology and function of excitatory cells. Therefore, it is important to develop an efficient cochlear implant electroacoustic stimulation (EAS) system to study the behavior of SGNs. In this work, we present an electrical stimulation system constructed by combining a cochlear implant and a conductive Ti3C2Tx MXene-matrigel hydrogel. SGNs were cultured in the Ti3C2Tx MXene-matrigel hydrogel and exposed to electrical stimulation transduced by the cochlear implant. It was demonstrated that low-frequency stimulation promoted the growth cone development and neurite outgrowth of SGNs as well as signal transmission between cells. This work may have potential value for the clinical application of the Ti3C2Tx MXene hydrogel to optimize the postoperative listening effect of cochlear implantation and benefit people with sensorineural hearing loss.
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Affiliation(s)
- Menghui Liao
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
- Department
of Otorhinolaryngology−Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China
| | - Yangnan Hu
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
- Department
of Otorhinolaryngology−Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China
| | - Yuhua Zhang
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
| | - Kaichen Wang
- Chien-Shiung
Wu College, Southeast University, Nanjing, Jiangsu 210096, China
| | - Qiaojun Fang
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
| | - Yanru Qi
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
| | - Yingbo Shen
- Chien-Shiung
Wu College, Southeast University, Nanjing, Jiangsu 210096, China
| | - Hong Cheng
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
| | - Xiaolong Fu
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
| | - Mingliang Tang
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
- Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Affiliated
Hospital, Medical College, Soochow University, Suzhou, Jiangsu 215000, China
- Co-Innovation
Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
| | - Shan Sun
- ENT
Institute and Department
of Otorhinolaryngology, Eye and ENT Hospital, State Key Laboratory
of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China
| | - Xia Gao
- Department
of Otorhinolaryngology−Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China
| | - Renjie Chai
- State
Key Laboratory of Bioelectronics, Department of Otolaryngology Head
and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology,
Advanced Institute for Life and Health, Jiangsu Province High-Tech
Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China
- Co-Innovation
Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
- Department
of Otolaryngology−Head and Neck Surgery, Sichuan Provincial
People’s Hospital, University of
Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Institute
for Stem Cell and Regeneration, Chinese
Academy of Science, Beijing 100101, China
- Beijing
Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China
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16
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Emerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration. Int J Mol Sci 2022; 23:ijms232012393. [PMID: 36293251 PMCID: PMC9604452 DOI: 10.3390/ijms232012393] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/14/2022] [Indexed: 11/05/2022] Open
Abstract
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.
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17
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Wolf BJ, Kusch K, Hunniford V, Vona B, Kühler R, Keppeler D, Strenzke N, Moser T. Is there an unmet medical need for improved hearing restoration? EMBO Mol Med 2022; 14:e15798. [PMID: 35833443 PMCID: PMC9358394 DOI: 10.15252/emmm.202215798] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/12/2022] [Accepted: 06/02/2022] [Indexed: 12/26/2022] Open
Abstract
Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade.
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Affiliation(s)
- Bettina Julia Wolf
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Göttingen, Germany.,Auditory Neuroscience & Synaptic Nanophysiology Group, Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany.,Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
| | - Kathrin Kusch
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Functional Auditory Genomics Group, Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Göttingen, Germany
| | - Victoria Hunniford
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Sensory and Motor Neuroscience PhD Program, Göttingen Graduate Center for Neurosciences, Biophysics, and Molecular Biosciences, Göttingen, Germany
| | - Barbara Vona
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Robert Kühler
- Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany
| | - Daniel Keppeler
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Auditory Neuroscience & Synaptic Nanophysiology Group, Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Nicola Strenzke
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.,Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
| | - Tobias Moser
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Göttingen, Germany.,Auditory Neuroscience & Synaptic Nanophysiology Group, Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany.,Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.,Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
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18
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Abstract
It is well established that humans and other mammals are minimally regenerative compared with organisms such as zebrafish, salamander or amphibians. In recent years, however, the identification of regenerative potential in neonatal mouse tissues that normally heal poorly in adults has transformed our understanding of regenerative capacity in mammals. In this Review, we survey the mammalian tissues for which regenerative or improved neonatal healing has been established, including the heart, cochlear hair cells, the brain and spinal cord, and dense connective tissues. We also highlight common and/or tissue-specific mechanisms of neonatal regeneration, which involve cells, signaling pathways, extracellular matrix, immune cells and other factors. The identification of such common features across neonatal tissues may direct therapeutic strategies that will be broadly applicable to multiple adult tissues.
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Affiliation(s)
| | - Alice H. Huang
- Department of Orthopedic Surgery, Columbia University, New York, NY 10032, USA
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19
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Chen J, Gao D, Chen J, Hou S, He B, Li Y, Li S, Zhang F, Sun X, Jin Y, Sun L, Yang J. Pseudo-Temporal Analysis of Single-Cell RNA Sequencing Reveals Trans-Differentiation Potential of Greater Epithelial Ridge Cells Into Hair Cells During Postnatal Development of Cochlea in Rats. Front Mol Neurosci 2022; 15:832813. [PMID: 35370544 PMCID: PMC8966675 DOI: 10.3389/fnmol.2022.832813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/08/2022] [Indexed: 11/23/2022] Open
Abstract
The hair cells of the cochlea play a decisive role in the process of hearing damage and recovery, yet knowledge of their regeneration process is still limited. Greater epithelial ridge (GER) cells, a type of cell present during cochlear development that has the characteristics of a precursor sensory cell, disappear at the time of maturation of hearing development. Its development and evolution remain mysterious for many years. Here, we performed single-cell RNA sequencing to profile the gene expression landscapes of rats’ cochlear basal membrane from P1, P7, and P14 and identified eight major subtypes of GER cells. Furthermore, single-cell trajectory analysis for GER cells and hair cells indicated that among the different subtypes of GER, four subtypes had transient cell proliferation after birth and could transdifferentiate into inner and outer hair cells, and two of them mainly transdifferentiated into inner hair cells. The other two subtypes eventually transdifferentiate into outer hair cells. Our study lays the groundwork for elucidating the mechanisms of the key regulatory genes and signaling pathways in the trans-differentiation of GER cell subtypes into hair cells and provides potential clues to understand hair cell regeneration.
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Affiliation(s)
- Jianyong Chen
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Dekun Gao
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Junmin Chen
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Shule Hou
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Baihui He
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Yue Li
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Shuna Li
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Fan Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Xiayu Sun
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
| | - Yulian Jin
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
- *Correspondence: Yulian Jin,
| | - Lianhua Sun
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
- Lianhua Sun,
| | - Jun Yang
- Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Ear Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Otolaryngology and Translational Medicine, Shanghai, China
- Jun Yang,
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20
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Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss. Proc Natl Acad Sci U S A 2022; 119:e2107357119. [PMID: 35238644 PMCID: PMC8917383 DOI: 10.1073/pnas.2107357119] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Significance The mechanistic target of rapamycin (mTOR) plays a central role in growth, metabolism, and aging. It is assembled into two multiprotein complexes, namely, mTORC1 and mTORC2. We previously demonstrated the efficacy of sirolimus in ARHL in mice by decreasing mTORC1. However, the aspect of mTORC2 regulation in the cochlea is poorly characterized. Herein, based on pharmacological and genetic interventions, we found that a high dose of sirolimus resulted in severe hearing loss by reducing the mTORC2/AKT signaling pathway in the cochlea. Furthermore, selective activation of mTORC2 could protect against hearing loss induced by acoustic trauma and cisplatin-induced ototoxicity. Hence, the therapeutic activation of mTORC2 in conjunction with decreasing mTORC1 might represent a promising and effective strategy in preventing hearing loss.
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21
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Yang H, Zhu Y, Ye Y, Guan J, Min X, Xiong H. Nitric oxide protects against cochlear hair cell damage and noise-induced hearing loss through glucose metabolic reprogramming. Free Radic Biol Med 2022; 179:229-241. [PMID: 34801666 DOI: 10.1016/j.freeradbiomed.2021.11.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 11/08/2021] [Accepted: 11/17/2021] [Indexed: 11/25/2022]
Abstract
Nitric oxide (NO) is critically involved in the regulation of a wide variety of physiological and pathophysiological processes. However, the role of NO in the pathogenesis of noise-induced hearing loss (NIHL) is complex and remains controversial. Here we reported that treatment of CBA/J mice with l-arginine, a physiological precursor of NO, significantly reduced noise-induced reactive oxygen species accumulation in outer hair cells (OHCs), attenuated noise-induced loss of OHCs and NIHL consequently. Conversely, pharmacological inhibition of endothelial nitric oxide synthase exacerbated noise-induced loss of OHCs and aggravated NIHL. In HEI-OC1 cells, NO also showed substantial protection against H2O2-induced oxidative stress and cytotoxicity. Mechanistically, NO increased S-nitrosylation of pyruvate kinase M2 (PKM2) and inhibited its activity, which thus diverted glucose metabolic flux from glycolysis into the pentose phosphate pathway to increase production of reducing equivalents (NADPH and GSH) and eventually prevented H2O2-induced oxidative damage. These findings open new avenues for protection of cochlear hair cells from oxidative stress and prevention of NIHL through NO modulation of PKM2 and glucose metabolism reprogramming.
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Affiliation(s)
- Haidi Yang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China
| | - Yafeng Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongyi Ye
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiao Guan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Min
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China
| | - Hao Xiong
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China.
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22
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Knipper M, Singer W, Schwabe K, Hagberg GE, Li Hegner Y, Rüttiger L, Braun C, Land R. Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition. Front Neural Circuits 2022; 15:785603. [PMID: 35069123 PMCID: PMC8770933 DOI: 10.3389/fncir.2021.785603] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/08/2021] [Indexed: 12/19/2022] Open
Abstract
Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity is associated with numerous forms of hearing loss, including noise damage, age-dependent hearing loss, and deafness, as well as tinnitus or auditory processing deficits in autism spectrum disorder (ASD). In most cases, the reduced central inhibitory activity and the accompanying hyperexcitability are interpreted as an active compensatory response to the absence of synaptic activity, linked to increased central neural gain control (increased output activity relative to reduced input). We here suggest that hyperexcitability also could be related to an immaturity or impairment of tonic inhibitory strength that typically develops in an activity-dependent process in the ascending auditory pathway with auditory experience. In these cases, high-SR auditory nerve fibers, which are critical for the shortest latencies and lowest sound thresholds, may have either not matured (possibly in congenital deafness or autism) or are dysfunctional (possibly after sudden, stressful auditory trauma or age-dependent hearing loss linked with cognitive decline). Fast auditory processing deficits can occur despite maintained basal hearing. In that case, tonic inhibitory strength is reduced in ascending auditory nuclei, and fast inhibitory parvalbumin positive interneuron (PV-IN) dendrites are diminished in auditory and frontal brain regions. This leads to deficits in central neural gain control linked to hippocampal LTP/LTD deficiencies, cognitive deficits, and unbalanced extra-hypothalamic stress control. Under these conditions, a diminished inhibitory strength may weaken local neuronal coupling to homeostatic vascular responses required for the metabolic support of auditory adjustment processes. We emphasize the need to distinguish these two states of excitatory/inhibitory imbalance in hearing disorders: (i) Under conditions of preserved fast auditory processing and sustained tonic inhibitory strength, an excitatory/inhibitory imbalance following auditory deprivation can maintain precise hearing through a memory linked, transient disinhibition that leads to enhanced spiking fidelity (central neural gain⇑) (ii) Under conditions of critically diminished fast auditory processing and reduced tonic inhibitory strength, hyperexcitability can be part of an increased synchronization over a broader frequency range, linked to reduced spiking reliability (central neural gain⇓). This latter stage mutually reinforces diminished metabolic support for auditory adjustment processes, increasing the risks for canonical dementia syndromes.
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Affiliation(s)
- Marlies Knipper
- Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Center (THRC), Molecular Physiology of Hearing, University of Tübingen, Tübingen, Germany
- *Correspondence: Marlies Knipper,
| | - Wibke Singer
- Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Center (THRC), Molecular Physiology of Hearing, University of Tübingen, Tübingen, Germany
| | - Kerstin Schwabe
- Experimental Neurosurgery, Department of Neurosurgery, Hannover Medical School, Hanover, Germany
| | - Gisela E. Hagberg
- Department of Biomedical Magnetic Resonance, University Hospital Tübingen (UKT), Tübingen, Germany
- High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Tübingen, Germany
| | - Yiwen Li Hegner
- MEG Center, University of Tübingen, Tübingen, Germany
- Center of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Lukas Rüttiger
- Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Center (THRC), Molecular Physiology of Hearing, University of Tübingen, Tübingen, Germany
| | - Christoph Braun
- MEG Center, University of Tübingen, Tübingen, Germany
- Center of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Rüdiger Land
- Department of Experimental Otology, Institute for Audioneurotechnology, Hannover Medical School, Hanover, Germany
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23
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He Z, Ding Y, Mu Y, Xu X, Kong W, Chai R, Chen X. Stem Cell-Based Therapies in Hearing Loss. Front Cell Dev Biol 2021; 9:730042. [PMID: 34746126 PMCID: PMC8567027 DOI: 10.3389/fcell.2021.730042] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/04/2021] [Indexed: 12/19/2022] Open
Abstract
In recent years, neural stem cell transplantation has received widespread attention as a new treatment method for supplementing specific cells damaged by disease, such as neurodegenerative diseases. A number of studies have proved that the transplantation of neural stem cells in multiple organs has an important therapeutic effect on activation and regeneration of cells, and restore damaged neurons. This article describes the methods for inducing the differentiation of endogenous and exogenous stem cells, the implantation operation and regulation of exogenous stem cells after implanted into the inner ear, and it elaborates the relevant signal pathways of stem cells in the inner ear, as well as the clinical application of various new materials. At present, stem cell therapy still has limitations, but the role of this technology in the treatment of hearing diseases has been widely recognized. With the development of related research, stem cell therapy will play a greater role in the treatment of diseases related to the inner ear.
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Affiliation(s)
- Zuhong He
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yanyan Ding
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yurong Mu
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxiang Xu
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Weijia Kong
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Renjie Chai
- State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China
| | - Xiong Chen
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
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24
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Guo L, Cao W, Niu Y, He S, Chai R, Yang J. Autophagy Regulates the Survival of Hair Cells and Spiral Ganglion Neurons in Cases of Noise, Ototoxic Drug, and Age-Induced Sensorineural Hearing Loss. Front Cell Neurosci 2021; 15:760422. [PMID: 34720884 PMCID: PMC8548757 DOI: 10.3389/fncel.2021.760422] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) are the core components of the auditory system. However, they are vulnerable to genetic defects, noise exposure, ototoxic drugs and aging, and loss or damage of HCs and SGNs results in permanent hearing loss due to their limited capacity for spontaneous regeneration in mammals. Many efforts have been made to combat hearing loss including cochlear implants, HC regeneration, gene therapy, and antioxidant drugs. Here we review the role of autophagy in sensorineural hearing loss and the potential targets related to autophagy for the treatment of hearing loss.
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Affiliation(s)
- Lingna Guo
- State Key Laboratory of Bioelectronics, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Cao
- Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuguang Niu
- Department of Ambulatory Medicine, The First Medical Center of PLA General Hospital, Beijing, China
| | - Shuangba He
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Renjie Chai
- State Key Laboratory of Bioelectronics, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China
| | - Jianming Yang
- Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
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25
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Kwan KY, White PM. Understanding the differentiation and epigenetics of cochlear sensory progenitors in pursuit of regeneration. Curr Opin Otolaryngol Head Neck Surg 2021; 29:366-372. [PMID: 34374667 PMCID: PMC8452321 DOI: 10.1097/moo.0000000000000741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW Sensory hair cells (HCs) of the inner ear are responsible for our ability to hear and balance. Loss of these cells results in hearing loss. Stem cell replacement and in situ regeneration have the potential to replace lost HCs. Newly discovered contributions of transcription factor regulatory networks and epigenetic mechanisms in regulating HC differentiation and regeneration are placed into context of the literature. RECENT FINDINGS A wealth of new data has helped to define cochlear sensory progenitors in their developmental trajectories. This includes transcription factor networks, epigenetic manipulations, and cochlear HC subtype specification. SUMMARY Understanding how sensory progenitors differ and how HC subtypes arise will substantially inform efforts in hearing restoration.
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Affiliation(s)
- Kelvin Y. Kwan
- Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, New Jersey
| | - Patricia M. White
- Department of Neuroscience, Ernest J. Del Monte Institute of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
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26
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Keppeler D, Schwaerzle M, Harczos T, Jablonski L, Dieter A, Wolf B, Ayub S, Vogl C, Wrobel C, Hoch G, Abdellatif K, Jeschke M, Rankovic V, Paul O, Ruther P, Moser T. Multichannel optogenetic stimulation of the auditory pathway using microfabricated LED cochlear implants in rodents. Sci Transl Med 2021; 12:12/553/eabb8086. [PMID: 32718992 DOI: 10.1126/scitranslmed.abb8086] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/03/2020] [Indexed: 12/28/2022]
Abstract
When hearing fails, electrical cochlear implants (eCIs) provide the brain with auditory information. One important bottleneck of CIs is the poor spectral selectivity that results from the wide current spread from each of the electrode contacts. Optical CIs (oCIs) promise to make better use of the tonotopic order of spiral ganglion neurons (SGNs) inside the cochlea by spatially confined stimulation. Here, we established multichannel oCIs based on light-emitting diode (LED) arrays and used them for optical stimulation of channelrhodopsin (ChR)-expressing SGNs in rodents. Power-efficient blue LED chips were integrated onto microfabricated 15-μm-thin polyimide-based carriers comprising interconnecting lines to address individual LEDs by a stationary or mobile driver circuitry. We extensively characterized the optoelectronic, thermal, and mechanical properties of the oCIs and demonstrated stability over weeks in vitro. We then implanted the oCIs into ChR-expressing rats and gerbils, and characterized multichannel optogenetic SGN stimulation by electrophysiological and behavioral experiments. Improved spectral selectivity was directly demonstrated by recordings from the auditory midbrain. Long-term experiments in deafened ChR-expressing rats and in nontreated control animals demonstrated specificity of optogenetic stimulation. Behavioral studies on animals carrying a wireless oCI sound processor revealed auditory percepts. This study demonstrates hearing restoration with improved spectral selectivity by an LED-based multichannel oCI system.
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Affiliation(s)
- Daniel Keppeler
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Göttingen Graduate Center for Neurosciences and Molecular Biosciences, University of Göttingen, 37075 Göttingen, Germany
| | - Michael Schwaerzle
- University of Freiburg, Department of Microsystems Engineering (IMTEK), 79110 Freiburg, Germany.,Cluster of Excellence BrainLinks-BrainTools, University of Freiburg, 79110 Freiburg, Germany
| | - Tamas Harczos
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Lukasz Jablonski
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Alexander Dieter
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Göttingen Graduate Center for Neurosciences and Molecular Biosciences, University of Göttingen, 37075 Göttingen, Germany
| | - Bettina Wolf
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Suleman Ayub
- University of Freiburg, Department of Microsystems Engineering (IMTEK), 79110 Freiburg, Germany.,Cluster of Excellence BrainLinks-BrainTools, University of Freiburg, 79110 Freiburg, Germany
| | - Christian Vogl
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Collaborative Research Center 889, University of Göttingen, 37075 Göttingen, Germany
| | - Christian Wrobel
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Gerhard Hoch
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Khaled Abdellatif
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Marcus Jeschke
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Vladan Rankovic
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany
| | - Oliver Paul
- University of Freiburg, Department of Microsystems Engineering (IMTEK), 79110 Freiburg, Germany.,Cluster of Excellence BrainLinks-BrainTools, University of Freiburg, 79110 Freiburg, Germany
| | - Patrick Ruther
- University of Freiburg, Department of Microsystems Engineering (IMTEK), 79110 Freiburg, Germany. .,Cluster of Excellence BrainLinks-BrainTools, University of Freiburg, 79110 Freiburg, Germany
| | - Tobias Moser
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany. .,Göttingen Graduate Center for Neurosciences and Molecular Biosciences, University of Göttingen, 37075 Göttingen, Germany.,Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany.,Collaborative Research Center 889, University of Göttingen, 37075 Göttingen, Germany.,Multiscale Bioimaging Cluster of Excellence, University Medical Center Göttingen, 37075 Göttingen, Germany.,MPI for Biophysical Chemistry, 37077 Göttingen, Germany
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27
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Hauber ME, Louder MI, Griffith SC. Neurogenomic insights into the behavioral and vocal development of the zebra finch. eLife 2021; 10:61849. [PMID: 34106827 PMCID: PMC8238503 DOI: 10.7554/elife.61849] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 06/08/2021] [Indexed: 02/06/2023] Open
Abstract
The zebra finch (Taeniopygia guttata) is a socially monogamous and colonial opportunistic breeder with pronounced sexual differences in singing and plumage coloration. Its natural history has led to it becoming a model species for research into sex differences in vocal communication, as well as behavioral, neural and genomic studies of imitative auditory learning. As scientists tap into the genetic and behavioral diversity of both wild and captive lineages, the zebra finch will continue to inform research into culture, learning, and social bonding, as well as adaptability to a changing climate.
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Affiliation(s)
- Mark E Hauber
- Department of Evolution, Ecology, and Behavior, School of Integrative Biology, University of Illinois at Urbana-Champaign, Urbana-Champaign, United States
| | - Matthew Im Louder
- International Research Center for Neurointelligence, University of Tokyo, Tokyo, Japan.,Department of Biology, Texas A&M University, College Station, United States
| | - Simon C Griffith
- Department of Biological Sciences, Macquarie University, Sydney, Australia
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28
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Stojkovic M, Han D, Jeong M, Stojkovic P, Stankovic KM. Human induced pluripotent stem cells and CRISPR/Cas-mediated targeted genome editing: Platforms to tackle sensorineural hearing loss. STEM CELLS (DAYTON, OHIO) 2021; 39:673-696. [PMID: 33586253 DOI: 10.1002/stem.3353] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/13/2020] [Indexed: 11/09/2022]
Abstract
Hearing loss (HL) is a major global health problem of pandemic proportions. The most common type of HL is sensorineural hearing loss (SNHL) which typically occurs when cells within the inner ear are damaged. Human induced pluripotent stem cells (hiPSCs) can be generated from any individual including those who suffer from different types of HL. The development of new differentiation protocols to obtain cells of the inner ear including hair cells (HCs) and spiral ganglion neurons (SGNs) promises to expedite cell-based therapy and screening of potential pharmacologic and genetic therapies using human models. Considering age-related, acoustic, ototoxic, and genetic insults which are the most frequent causes of irreversible damage of HCs and SGNs, new methods of genome editing (GE), especially the CRISPR/Cas9 technology, could bring additional opportunities to understand the pathogenesis of human SNHL and identify novel therapies. However, important challenges associated with both hiPSCs and GE need to be overcome before scientific discoveries are correctly translated to effective and patient-safe applications. The purpose of the present review is (a) to summarize the findings from published reports utilizing hiPSCs for studies of SNHL, hence complementing recent reviews focused on animal studies, and (b) to outline promising future directions for deciphering SNHL using disruptive molecular and genomic technologies.
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Affiliation(s)
- Miodrag Stojkovic
- Eaton Peabody Laboratories, Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, USA.,Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Dongjun Han
- Eaton Peabody Laboratories, Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, USA.,Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Minjin Jeong
- Eaton Peabody Laboratories, Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, USA.,Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Petra Stojkovic
- Eaton Peabody Laboratories, Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, USA.,Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Konstantina M Stankovic
- Eaton Peabody Laboratories, Department of Otolaryngology Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, USA.,Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA.,Program in Speech and Hearing Bioscience and Technology, Harvard University, Cambridge, Massachusetts, USA.,Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
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29
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Janesick A, Scheibinger M, Benkafadar N, Kirti S, Ellwanger DC, Heller S. Cell-type identity of the avian cochlea. Cell Rep 2021; 34:108900. [PMID: 33761346 DOI: 10.1016/j.celrep.2021.108900] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/22/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
In contrast to mammals, birds recover naturally from acquired hearing loss, which makes them an ideal model for inner ear regeneration research. Here, we present a validated single-cell RNA sequencing resource of the avian cochlea. We describe specific markers for three distinct types of sensory hair cells, including a previously unknown subgroup, which we call superior tall hair cells. We identify markers for the supporting cells associated with tall hair cells, which represent the facultative stem cells of the avian inner ear. Likewise, we present markers for supporting cells that are located below the short cochlear hair cells. We further infer spatial expression gradients of hair cell genes along the tonotopic axis of the cochlea. This resource advances neurobiology, comparative biology, and regenerative medicine by providing a basis for comparative studies with non-regenerating mammalian cochleae and for longitudinal studies of the regenerating avian cochlea.
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Affiliation(s)
- Amanda Janesick
- Department of Otolaryngology - Head & Neck Surgery, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
| | - Mirko Scheibinger
- Department of Otolaryngology - Head & Neck Surgery, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Nesrine Benkafadar
- Department of Otolaryngology - Head & Neck Surgery, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Sakin Kirti
- Department of Otolaryngology - Head & Neck Surgery, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Case Western Reserve University, Cleveland, OH 44106, USA
| | - Daniel C Ellwanger
- Department of Otolaryngology - Head & Neck Surgery, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Genome Analysis Unit, Amgen Research, Amgen, Inc., South San Francisco, CA 94080, USA
| | - Stefan Heller
- Department of Otolaryngology - Head & Neck Surgery, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
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30
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Abstract
Electric-acoustic stimulation (EAS) is a special treatment modality for those patients who are profoundly deaf in the high-frequency (HF) region and retain usable hearing in the low-frequency (LF) region. Combining the electric stimulation with cochlear implant (CI) in the HF and acoustic amplification of residual hearing using a conventional hearing aid (HA) in the LF region defines EAS. The EAS concept was first proposed by C. von Ilberg from Frankfurt, Germany in the year 1997. In association with MED-EL, all the necessary safety studies were performed in non-human subjects before the first patient received it in 1997. In association with MED-EL, all the necessary safety studies were performed in non-human subjects before the first patient received it in 1999. For the patient to successfully use the EAS concept, the residual hearing needs to be preserved to a high extent and for several years. This requires a highly flexible electrode array in safeguarding the intra-cochlear structures during and after the CI electrode array insertion. Combining the HA unit with the audio processor unit of the CI was necessary for the convenient wearing of the unified audio processor. Fitting of the unified audio processor is another important factor that contributes to the overall success of the EAS treatment. The key translational research efforts at MED-EL were on the development of flexible electrodes, a unified audio processor, innovations in the fitting process, intra-operative monitoring of cochlear health during electrode insertion, pre-operative soft-ware tool to evaluate the cochlear size and electrode selection and some new innovations tried within EAS topic. This article covers the milestones of translational research from the first concept to the widespread clinical use of EAS.
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Affiliation(s)
| | - Ingeborg Hochmair
- MED-EL Elektromedizinische Geraete Gesellschaft m.b.H., Innsbruck, Austria
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31
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Kubota M, Scheibinger M, Jan TA, Heller S. Greater epithelial ridge cells are the principal organoid-forming progenitors of the mouse cochlea. Cell Rep 2021; 34:108646. [PMID: 33472062 PMCID: PMC7847202 DOI: 10.1016/j.celrep.2020.108646] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/01/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
In mammals, hearing loss is irreversible due to the lack of regenerative potential of non-sensory cochlear cells. Neonatal cochlear cells, however, can grow into organoids that harbor sensory epithelial cells, including hair cells and supporting cells. Here, we purify different cochlear cell types from neonatal mice, validate the composition of the different groups with single-cell RNA sequencing (RNA-seq), and assess the various groups' potential to grow into inner ear organoids. We find that the greater epithelial ridge (GER), a transient cell population that disappears during post-natal cochlear maturation, harbors the most potent organoid-forming cells. We identified three distinct GER cell groups that correlate with a specific spatial distribution of marker genes. Organoid formation was synergistically enhanced when the cells were cultured at increasing density. This effect is not due to diffusible signals but requires direct cell-to-cell contact. Our findings improve the development of cell-based assays to study culture-generated inner ear cell types.
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Affiliation(s)
- Marie Kubota
- Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Mirko Scheibinger
- Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Taha A Jan
- Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Otolaryngology - Head & Neck Surgery, University of California San Francisco, San Francisco, CA 94115, USA
| | - Stefan Heller
- Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Xiong H, Lai L, Ye Y, Zheng Y. Glucose Protects Cochlear Hair Cells Against Oxidative Stress and Attenuates Noise-Induced Hearing Loss in Mice. Neurosci Bull 2021; 37:657-668. [PMID: 33415566 DOI: 10.1007/s12264-020-00624-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022] Open
Abstract
Oxidative stress is the key determinant in the pathogenesis of noise-induced hearing loss (NIHL). Given that cellular defense against oxidative stress is an energy-consuming process, the aim of the present study was to investigate whether increasing energy availability by glucose supplementation protects cochlear hair cells against oxidative stress and attenuates NIHL. Our results revealed that glucose supplementation reduced the noise-induced formation of reactive oxygen species (ROS) and consequently attenuated noise-induced loss of outer hair cells, inner hair cell synaptic ribbons, and NIHL in CBA/J mice. In cochlear explants, glucose supplementation increased the levels of ATP and NADPH, as well as attenuating H2O2-induced ROS production and cytotoxicity. Moreover, pharmacological inhibition of glucose transporter type 1 activity abolished the protective effects of glucose against oxidative stress in HEI-OC1 cells. These findings suggest that energy availability is crucial for oxidative stress resistance and glucose supplementation offers a simple and effective approach for the protection of cochlear hair cells against oxidative stress and NIHL.
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Affiliation(s)
- Hao Xiong
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120, China
| | - Lan Lai
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yongyi Ye
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yiqing Zheng
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. .,Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120, China.
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Askew C, Chien WW. Adeno-associated virus gene replacement for recessive inner ear dysfunction: Progress and challenges. Hear Res 2020; 394:107947. [PMID: 32247629 PMCID: PMC7939749 DOI: 10.1016/j.heares.2020.107947] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 03/02/2020] [Accepted: 03/04/2020] [Indexed: 01/08/2023]
Abstract
Approximately 3 in 1000 children in the US under 4 years of age are affected by hearing loss. Currently, cochlear implants represent the only line of treatment for patients with severe to profound hearing loss, and there are no targeted drug or biological based therapies available. Gene replacement is a promising therapeutic approach for hereditary hearing loss, where viral vectors are used to deliver functional cDNA to "replace" defective genes in dysfunctional cells in the inner ear. Proof-of-concept studies have successfully used this approach to improve auditory function in mouse models of hereditary hearing loss, and human clinical trials are on the immediate horizon. The success of this method is ultimately determined by the underlying biology of the defective gene and design of the treatment strategy, relying on intervention before degeneration of the sensory structures occurs. A challenge will be the delivery of a corrective gene to the proper target within the therapeutic window of opportunity, which may be unique for each specific defective gene. Although rescue of pre-lingual forms of recessive deafness have been explored in animal models thus far, future identification of genes with post-lingual onset that are amenable to gene replacement holds even greater promise for treatment, since the therapeutic window is likely open for a much longer period of time. This review summarizes the current state of adeno-associated virus (AAV) gene replacement therapy for recessive hereditary hearing loss and discusses potential challenges and opportunities for translating inner ear gene replacement therapy for patients with hereditary hearing loss.
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Affiliation(s)
- Charles Askew
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Wade W Chien
- Inner Ear Gene Therapy Program, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, USA; Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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Zhang S, Qiang R, Dong Y, Zhang Y, Chen Y, Zhou H, Gao X, Chai R. Hair cell regeneration from inner ear progenitors in the mammalian cochlea. AMERICAN JOURNAL OF STEM CELLS 2020; 9:25-35. [PMID: 32699655 PMCID: PMC7364385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/10/2020] [Indexed: 06/11/2023]
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.
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Affiliation(s)
- Shasha Zhang
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast UniversityNanjing 210096, China
| | - Ruiying Qiang
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast UniversityNanjing 210096, China
| | - Ying Dong
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast UniversityNanjing 210096, China
| | - Yuan Zhang
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast UniversityNanjing 210096, China
| | - Yin Chen
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210008, China
| | - Han Zhou
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210008, China
| | - Xia Gao
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210008, China
| | - Renjie Chai
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast UniversityNanjing 210096, China
- Co-Innovation Center of Neuroregeneration, Nantong UniversityNantong 226001, China
- Institute for Stem Cell and Regeneration, Chinese Academy of ScienceBeijing, China
- Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast UniversityNanjing 211189, China
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210008, China
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Jiang P, Zhang S, Cheng C, Gao S, Tang M, Lu L, Yang G, Chai R. The Roles of Exosomes in Visual and Auditory Systems. Front Bioeng Biotechnol 2020; 8:525. [PMID: 32582658 PMCID: PMC7283584 DOI: 10.3389/fbioe.2020.00525] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/04/2020] [Indexed: 12/16/2022] Open
Abstract
Exosomes are nanoscale membrane-enclosed vesicles 30-150 nm in diameter that are originated from a number of type cells by the endocytic pathway and consist of proteins, lipids, RNA, and DNA. Although, exosomes were initially considered to be cellular waste, they have gradually been recognized to join in cell-cell communication and cell signal transmission. In addition, exosomal contents can be applied as biomarkers for clinical judgment and exosomes can as potential carriers in a novel drug delivery system. Unfortunately, purification methods of exosomes remain an obstacle. We described some common purification methods and highlight Morpho Menelaus (M. Menelaus) butterfly wings can be developed as efficient methods for exosome isolation. Furthermore, the current research on exosomes mainly focused on their roles in cancer, while related studies on exosomes in the visual and auditory systems are limited. Here we reviewed the biogenesis and contents of exosomes. And more importantly, we summarized the roles of exosomes and provided prospective for exosome research in the visual and auditory systems.
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Affiliation(s)
- Pei Jiang
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
| | - Shasha Zhang
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
| | - Cheng Cheng
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, China.,Research Institute of Otolaryngology, Nanjing, China
| | - Song Gao
- Department of Otolaryngology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Mingliang Tang
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Cardiovascular Science, Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, China
| | - Ling Lu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, China
| | - Guang Yang
- Department of Otorhinolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China
| | - Renjie Chai
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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Senn P, Mina A, Volkenstein S, Kranebitter V, Oshima K, Heller S. Progenitor Cells from the Adult Human Inner Ear. Anat Rec (Hoboken) 2020; 303:461-470. [PMID: 31489779 PMCID: PMC7064943 DOI: 10.1002/ar.24228] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 02/18/2019] [Accepted: 04/30/2019] [Indexed: 11/10/2022]
Abstract
Loss of inner ear hair cells leads to incurable balance and hearing disorders because these sensory cells do not effectively regenerate in humans. A potential starting point for therapy would be the stimulation of quiescent progenitor cells within the damaged inner ear. Inner ear progenitor/stem cells, which have been described in rodent inner ears, would be principal candidates for such an approach. Despite the identification of progenitor cell populations in the human fetal cochlea and in the adult human spiral ganglion, no proliferative cell populations with the capacity to generate hair cells have been reported in vestibular and cochlear tissues of adult humans. The present study aimed at filling this gap by isolating colony-forming progenitor cells from surgery- and autopsy-derived adult human temporal bones in order to generate inner ear cell types in vitro. Sphere-forming and mitogen-responding progenitor cells were isolated from vestibular and cochlear tissues. Clonal spheres grown from adult human utricle and cochlear duct were propagated for a limited number of generations. When differentiated in absence of mitogens, the utricle-derived spheres robustly gave rise to hair cell-like cells, as well as to cells expressing supporting cell-, neuron-, and glial markers, indicating that the adult human utricle harbors multipotent progenitor cells. Spheres derived from the adult human cochlear duct did not give rise to hair cell-like or neuronal cell types, which is an indication that human cochlear cells have limited proliferative potential but lack the ability to differentiate into major inner ear cell types. Anat Rec, 303:461-470, 2020. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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Affiliation(s)
- Pascal Senn
- Department of Clinical Neurosciences, Service ORL & CCFUniversity hospital of GenevaGenevaSwitzerland
- University Department of Otorhinolaryngology, Head and Neck SurgeryInselspitalBernSwitzerland
- Department of Otolaryngology, Head and Neck SurgeryStanford UniversityPalo AltoCalifornia
- Department of Molecular and Cellular PhysiologyStanford UniversityPalo AltoCalifornia
| | - Amir Mina
- University Department of Otorhinolaryngology, Head and Neck SurgeryInselspitalBernSwitzerland
- University Department of Otorhinolaryngology, Head and Neck SurgeryAlexandria Faculty of MedicineAlexandriaEgypt
| | - Stefan Volkenstein
- Department of Otolaryngology, Head and Neck SurgeryStanford UniversityPalo AltoCalifornia
- Department of Molecular and Cellular PhysiologyStanford UniversityPalo AltoCalifornia
- Department of Otorhinolaryngology, Head and Neck SurgeryRuhr‐University of Bochum, St. Elisabeth‐HospitalBochumGermany
| | - Veronika Kranebitter
- Department of Otolaryngology, Head and Neck SurgeryStanford UniversityPalo AltoCalifornia
- Department of Molecular and Cellular PhysiologyStanford UniversityPalo AltoCalifornia
- Department of Otorhinolaryngology, Head and Neck SurgeryMedical University of ViennaViennaAustria
| | - Kazuo Oshima
- Department of Otolaryngology, Head and Neck SurgeryStanford UniversityPalo AltoCalifornia
- Department of Molecular and Cellular PhysiologyStanford UniversityPalo AltoCalifornia
- Department of Otorhinolaryngology, Head and Neck SurgeryOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Stefan Heller
- Department of Otolaryngology, Head and Neck SurgeryStanford UniversityPalo AltoCalifornia
- Department of Molecular and Cellular PhysiologyStanford UniversityPalo AltoCalifornia
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Cheng C, Wang Y, Guo L, Lu X, Zhu W, Muhammad W, Zhang L, Lu L, Gao J, Tang M, Chen F, Gao X, Li H, Chai R. Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea. Stem Cell Res Ther 2019; 10:365. [PMID: 31791390 PMCID: PMC6889721 DOI: 10.1186/s13287-019-1437-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/29/2019] [Accepted: 10/01/2019] [Indexed: 12/17/2022] Open
Abstract
Background Inner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages. Methods Here, we used Sox2GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis. Results Consistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration. Conclusions In our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.
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Affiliation(s)
- Cheng Cheng
- Jiangsu Provincial Key Medical Discipline (Laboratory), Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.,Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Yunfeng Wang
- Shanghai Fenyang Vision & Audition Center, Shanghai, China.,ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China
| | - Luo Guo
- ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China
| | - Xiaoling Lu
- ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China
| | - Weijie Zhu
- MOE Key Laboratory for Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Co-Innovation Center of Neuroregeneration, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Waqas Muhammad
- MOE Key Laboratory for Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Co-Innovation Center of Neuroregeneration, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.,Department of Biotechnology, Federal Urdu University of Arts, Science and Technology, Gulshan-e-Iqbal Campus, Karachi, Pakistan
| | - Liyan Zhang
- MOE Key Laboratory for Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Co-Innovation Center of Neuroregeneration, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Ling Lu
- Jiangsu Provincial Key Medical Discipline (Laboratory), Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Junyan Gao
- Jiangsu Rehabilitation Research Center for Hearing and Speech Impairment, Nanjing, 210004, Jiangsu, China
| | - Mingliang Tang
- MOE Key Laboratory for Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Co-Innovation Center of Neuroregeneration, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Fangyi Chen
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Xia Gao
- Jiangsu Provincial Key Medical Discipline (Laboratory), Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.
| | - Huawei Li
- ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China.
| | - Renjie Chai
- ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China. .,MOE Key Laboratory for Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Co-Innovation Center of Neuroregeneration, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China. .,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China. .,Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China.
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Preservation of Cells of the Organ of Corti and Innervating Dendritic Processes Following Cochlear Implantation in the Human: An Immunohistochemical Study. Otol Neurotol 2019; 39:284-293. [PMID: 29342037 DOI: 10.1097/mao.0000000000001686] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
HYPOTHESIS This study evaluates the degree of preservation of hair cells, supporting cells, and innervating dendritic processes after cochlear implantation in the human using immunohistochemical methods. BACKGROUND Surgical insertion of a cochlear implant electrode induces various pathologic changes within the cochlea including insertional trauma, foreign body response, inflammation, fibrosis, and neo-osteogenesis. These changes may result in loss of residual acoustic hearing, adversely affecting the use of hybrid implants, and may result in loss of putative precursor cells, limiting the success of future regenerative protocols. METHODS Twenty-eight celloidin-embedded temporal bones from 14 patients with bilateral severe to profound sensorineural hearing loss and unilateral cochlear implants were studied. Two sections including the modiolus or basal turn from each temporal bone were stained using antineurofilament, antimyosin-VIIa, and antitubulin antibodies in both the implanted and unimplanted ears. RESULTS Inner and outer hair cells: Immunoreactivity was reduced throughout the implanted cochlea and in the unimplanted cochlea with the exception of the apical turn.Dendritic processes in the osseous spiral lamina: Immunoreactivity was significantly less along the electrode of the implanted cochlea than in the other segments.Inner and outer pillars, inner and outer spiral bundles, and Deiters' cells: Immunoreactivity was similar in the implanted and unimplanted cochleae. CONCLUSION Insertion of a cochlear implant electrode may significantly affect the inner and outer hair cells both along and apical to the electrode, and dendritic processes in the osseous spiral lamina along the electrode. There was less effect on pillar cells, Deiters' cells, and spiral bundles.
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Abstract
Despite impressive technical progress in the field of conventional hearing aids and implantable hearing systems, the hopes for the treatment of inner ear diseases such as hearing loss and tinnitus have become increasingly directed toward regenerative therapeutic approaches. This review discusses the currently most promising strategies for hair cell regeneration in the inner ear to treat hearing loss, including stem cell-based, gene transfer-based, and pharmacological interventions. Furthermore, previous milestones and ground-breaking work in this scientific field are identified. After many years of basic research, the first clinical trials with a regenerative therapeutic approach for hearing-impaired patients were recently initiated. Although there is still a long and bumpy road ahead until a true breakthrough is achieved, it seems more realistic than ever that regenerative therapies for the inner ear will find their way into clinical practice.
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Affiliation(s)
- M Diensthuber
- Klinik für Hals-Nasen-Ohrenheilkunde, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt/M., Deutschland.
| | - T Stöver
- Klinik für Hals-Nasen-Ohrenheilkunde, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt/M., Deutschland
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Abstract
This review summarizes paleontological data as well as studies on the morphology, function, and molecular evolution of the cochlea of living mammals (monotremes, marsupials, and placentals). The most parsimonious scenario is an early evolution of the characteristic organ of Corti, with inner and outer hair cells and nascent electromotility. Most remaining unique features, such as loss of the lagenar macula, coiling of the cochlea, and bony laminae supporting the basilar membrane, arose later, after the separation of the monotreme lineage, but before marsupial and placental mammals diverged. The question of when hearing sensitivity first extended into the ultrasonic range (defined here as >20 kHz) remains speculative, not least because of the late appearance of the definitive mammalian middle ear. The last significant change was optimizing the operating voltage range of prestin, and thus the efficiency of the outer hair cells' amplifying action, in the placental lineage only.
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Affiliation(s)
- Christine Köppl
- Cluster of Excellence "Hearing4all" and Research Centre Neurosensory Science, Department of Neuroscience, School of Medicine and Health Science, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany
| | - Geoffrey A Manley
- Cluster of Excellence "Hearing4all" and Research Centre Neurosensory Science, Department of Neuroscience, School of Medicine and Health Science, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany
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Abd El Raouf HHH, Galhom RA, Ali MHM, Nasr El-Din WA. Harderian gland-derived stem cells as a cytotherapy in a guinea pig model of carboplatin-induced hearing loss. J Chem Neuroanat 2019; 98:139-152. [PMID: 31047945 DOI: 10.1016/j.jchemneu.2019.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 03/09/2019] [Accepted: 04/28/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Stem cells therapy of hearing loss is a challenging field due to lacking self-regenerative capacity of cochlea. Harderian gland of guinea pigs was thought to harbour a unique type of progenitors which could restore the damaged cochlear tissues. THE AIM of this study was to isolate Harderian gland derived stem cells (HG-SCs) and investigate their efficacy in restoring the damaged cochlear tissue in carboplatin-induced hearing loss. METHODOLOGY Sixty female and 10 male pigmented guinea pigs were used; the male animals were HG-SCs donors, while the females were assigned into 3 groups; control, hearing loss (HL) and HG-SC-treated groups. Auditory reflexes were assessed throughout the study. The animals were euthanized 35 days after HG-SCs transplantation, the cochleae were extracted and processed for assessment by light microscope and scanning electron microscope. Morphometric assessment of stria vascularis thickness, hair cells and spiral ganglia neuronal number and optical density of TLR4 expression were done. RESULTS The isolated HG-SCs had the same morphological and phenotypical character as mesenchymal stem cells. HL group revealed destruction of organ of Corti, stria vascularis and spiral ganglion with decreased morphometric parameters. Restoration of both cochlear structure and function was observed in HG-SC-treated group along with a significant increase in IHCs, OHCs numbers, stria vascularis thickness and spiral ganglionic cell count to be close to the values of control group. CONCLUSION The isolated HG-SCs were proved to restore structure and function of cochlea in guinea pig model of hearing loss.
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Affiliation(s)
| | - Rania A Galhom
- Human Anatomy and Embryology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Mona H Mohammed Ali
- Human Anatomy and Embryology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Wael Amin Nasr El-Din
- Human Anatomy and Embryology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Anatomy Department, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia
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Fetoni AR, Paciello F, Rolesi R, Paludetti G, Troiani D. Targeting dysregulation of redox homeostasis in noise-induced hearing loss: Oxidative stress and ROS signaling. Free Radic Biol Med 2019; 135:46-59. [PMID: 30802489 DOI: 10.1016/j.freeradbiomed.2019.02.022] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/04/2019] [Accepted: 02/18/2019] [Indexed: 12/20/2022]
Abstract
Hearing loss caused by exposure to recreational and occupational noise remains a worldwide disabling condition and dysregulation of redox homeostasis is the hallmark of cochlear damage induced by noise exposure. In this review we discuss the dual function of ROS to both promote cell damage (oxidative stress) and cell adaptive responses (ROS signaling) in the cochlea undergoing a stressful condition such as noise exposure. We focus on animal models of noise-induced hearing loss (NIHL) and on the function of exogenous antioxidants to maintaining a physiological role of ROS signaling by distinguishing the effect of exogenous "direct" antioxidants (i.e. CoQ10, NAC), that react with ROS to decrease oxidative stress, from the exogenous "indirect" antioxidants (i.e. nutraceutics and phenolic compounds) that can activate cellular redox enzymes through the Keap1-Nrf2-ARE pathway. The anti-inflammatory properties of Nrf2 signaling are discussed in relation to the ROS/inflammation interplay in noise exposure. Unveiling the mechanisms of ROS regulating redox-associated signaling pathways is essential in providing relevant targets for innovative and effective therapeutic strategies against NIHL.
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Affiliation(s)
- Anna Rita Fetoni
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, Italy; CNR Institute of Cell Biology and Neurobiology, Monterotondo, Italy
| | - Fabiola Paciello
- Institute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, Italy; CNR Institute of Cell Biology and Neurobiology, Monterotondo, Italy
| | - Rolando Rolesi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gaetano Paludetti
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Diana Troiani
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.
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Abstract
Increasing numbers of cochlear implant patients have residual hearing. Despite surgical and pharmacological efforts to preserve residual hearing, a significant number of these patients suffer a late, unexplained loss of residual hearing. Surgical trauma can be excluded as the cause. To investigate this phenomenon and because cells in their native environment react differently to stimuli (such as electrical current) than isolated cells, whole-organ explants from cochleae may be a better model. For early detection of synaptic changes in the organ of Corti, a high-resolution microscopic technique such as stimulated emission depletion (StED) can be used. The aim of this study was establishment of a qualitative and quantitative technique to determinate changes in the organ of Corti and its synapses after electrical stimulation. Explanted organs of Corti from postnatal rats (P2-4) were cultured on a coverslip for 24 h and subsequently exposed to biphasic pulsed electrical stimulation (amplitude 0.44-2.0 mA, pulse width 400 μs, interpulse delay 120 μs, repetition 1 kHz) for another 24 h. For visualization, the cytoskeleton and the ribbon synapses were stained immunocytochemically. For an early detectable response to electrical stimulation, the number of synapses was quantified. Organs of Corti without electrical stimulation served as a reference. Initial research has shown that electrical stimulation can cause changes in ribbon synapses and that StED can detect these alterations. The herein established model could be of great importance for identification of molecular changes in the organ of Corti in response to electrical or other stimuli.
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Abstract
Hearing loss is present in millions of people worldwide. Current treatment for patients with severe to profound hearing loss consists of cochlear implantation. Providing the cochlear nerve is intact, patients generally benefit greatly from this intervention, frequently achieving significant improvements in speech comprehension. There are, however, some cases where current technology does not provide patients with adequate benefit. Ongoing research in cell transplantation and gene therapy promises to lead to new developments that will improve the function of cochlear implants. Translation of these experimental approaches is presently at an early stage. This review focuses on the application of biological therapies in severe hearing loss and discusses some of the barriers to translating basic scientific research into clinical reality. We emphasize the application of these novel therapies to cochlear implantation.
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Affiliation(s)
- A Roemer
- Klinik für Hals-Nasen-Ohren-Heilkunde OE 6500, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - H Staecker
- Department of Otolaryngology - Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, KS, USA
| | - S Sasse
- Klinik für Hals-Nasen-Ohren-Heilkunde OE 6500, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - T Lenarz
- Klinik für Hals-Nasen-Ohren-Heilkunde OE 6500, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - A Warnecke
- Klinik für Hals-Nasen-Ohren-Heilkunde OE 6500, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
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Ralli M, Rolesi R, Anzivino R, Turchetta R, Fetoni AR. Acquired sensorineural hearing loss in children: current research and therapeutic perspectives. ACTA OTORHINOLARYNGOLOGICA ITALICA 2018; 37:500-508. [PMID: 29327735 PMCID: PMC5782428 DOI: 10.14639/0392-100x-1574] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 05/02/2017] [Indexed: 01/03/2023]
Abstract
The knowledge of mechanisms responsible for acquired sensorineural hearing loss in children, such as viral and bacterial infections, noise exposure, aminoglycoside and cisplatin ototoxicity, is increasing and progressively changing the clinical management of affected patients. Viral infections are by far the most relevant cause of acquired hearing loss, followed by aminoglycoside and platinum derivative ototoxicity; moreover, cochlear damage induced by noise overexposure, mainly in adolescents, is an emerging topic. Pharmacological approaches are still challenging to develop a truly effective cochlear protection; however, the use of steroids, antioxidants, antiviral drugs and other small molecules is encouraging for clinical practice. Most of evidence on the effectiveness of antioxidants is still limited to experimental models, while the use of corticosteroids and antiviral drugs has a wide correspondence in literature but with controversial safety. Future therapeutic perspectives include innovative strategies to transport drugs into the cochlea, such as molecules incorporated in nanoparticles that can be delivered to a specific target. Innovative approaches also include the gene therapy designed to compensate for abnormal genes or to make proteins by introducing genetic material into cells; finally, regenerative medicine (including stem cell approaches) may play a central role in the upcoming years in hearing preservation and restoration even if its role in the inner ear is still debated.
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Affiliation(s)
- M Ralli
- Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Italy
| | - R Rolesi
- Department of Otolaryngology, Catholic University of Sacred Heart, Rome, Italy
| | - R Anzivino
- Department of Otolaryngology, Catholic University of Sacred Heart, Rome, Italy
| | - R Turchetta
- Department of Sense Organs, Sapienza University of Rome, Italy
| | - A R Fetoni
- Department of Otolaryngology, Catholic University of Sacred Heart, Rome, Italy
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Hair cell identity establishes labeled lines of directional mechanosensation. PLoS Biol 2018; 16:e2004404. [PMID: 30024872 PMCID: PMC6067750 DOI: 10.1371/journal.pbio.2004404] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 07/31/2018] [Accepted: 07/02/2018] [Indexed: 11/19/2022] Open
Abstract
Directional mechanoreception by hair cells is transmitted to the brain via afferent neurons to enable postural control and rheotaxis. Neuronal tuning to individual directions of mechanical flow occurs when each peripheral axon selectively synapses with multiple hair cells of identical planar polarization. How such mechanosensory labeled lines are established and maintained remains unsolved. Here, we use the zebrafish lateral line to reveal that asymmetric activity of the transcription factor Emx2 diversifies hair cell identity to instruct polarity-selective synaptogenesis. Unexpectedly, presynaptic scaffolds and coherent hair cell orientation are dispensable for synaptic selectivity, indicating that epithelial planar polarity and synaptic partner matching are separable. Moreover, regenerating axons recapitulate synapses with hair cells according to Emx2 expression but not global orientation. Our results identify a simple cellular algorithm that solves the selectivity task even in the presence of noise generated by the frequent receptor cell turnover. They also suggest that coupling connectivity patterns to cellular identity rather than polarity relaxes developmental and evolutionary constraints to innervation of organs with differing orientation. Mechanosensory systems are essential for maintaining posture, gaze, and body orientation during locomotion. Such stability requires a coherent representation in the brain of the location and movement of mechanical stimuli. In fishes, mechanical stimuli at a given position activate direction-sensitive receptors called hair cells that are oriented with polarized directionality. These hair cells stimulate neurons that selectively connect with them based on polarity. We have addressed how neurons target hair cells based on polarity during development of the mechanosensory lateral line system in zebrafish. We show that neurons selectively connect based on the expression pattern of the transcription factor Emx2 in hair cells. We find that the lateral line can maintain directionality after damage and regeneration. Our data suggest a cellular mechanism that controls the formation, maintenance, and regeneration of labeled lines to enable directional mechanosensation.
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Zhang W, Kim SM, Wang W, Cai C, Feng Y, Kong W, Lin X. Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success. Front Mol Neurosci 2018; 11:221. [PMID: 29997477 PMCID: PMC6028713 DOI: 10.3389/fnmol.2018.00221] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 06/06/2018] [Indexed: 12/19/2022] Open
Abstract
Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants. These biologically-based interventions also carry the potential to re-establish hearing without the need for implanting any prosthetic device; the convenience and lower financial burden afforded by such biologically-based interventions could potentially benefit far more SNHL patients. Recently major progress has been achieved in preclinical studies of cochlear gene therapy. This review critically evaluates recent advances in the preclinical trials of gene therapies for SNHL and the major remaining challenges for the development and eventual clinical translation of this novel therapy. The cochlea bears many similarities to the eye for translational studies of gene therapies. Experience gained in ocular gene therapy trials, many of which have advanced to clinical phase III, may provide valuable guidance in improving the chance of success for cochlear gene therapy in human trials. A discussion on potential implications of translational knowledge gleaned from large numbers of advanced clinical trials of ocular gene therapy is therefore included.
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Affiliation(s)
- Wenjuan Zhang
- Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sun Myoung Kim
- Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, United States
| | - Wenwen Wang
- Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Yong Feng
- Xiangya School of Medicine, Changsha, China
| | - Weijia Kong
- Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Lin
- Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, United States
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Lahlou H, Lopez-Juarez A, Fontbonne A, Nivet E, Zine A. Modeling human early otic sensory cell development with induced pluripotent stem cells. PLoS One 2018; 13:e0198954. [PMID: 29902227 PMCID: PMC6002076 DOI: 10.1371/journal.pone.0198954] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 05/24/2018] [Indexed: 11/18/2022] Open
Abstract
The inner ear represents a promising system to develop cell-based therapies from human induced pluripotent stem cells (hiPSCs). In the developing ear, Notch signaling plays multiple roles in otic region specification and for cell fate determination. Optimizing hiPSC induction for the generation of appropriate numbers of otic progenitors and derivatives, such as hair cells, may provide an unlimited supply of cells for research and cell-based therapy. In this study, we used monolayer cultures, otic-inducing agents, Notch modulation, and marker expression to track early and otic sensory lineages during hiPSC differentiation. Otic/placodal progenitors were derived from hiPSC cultures in medium supplemented with FGF3/FGF10 for 13 days. These progenitor cells were then treated for 7 days with retinoic acid (RA) and epidermal growth factor (EGF) or a Notch inhibitor. The differentiated cultures were analyzed in parallel by qPCR and immunocytochemistry. After the 13 day induction, hiPSC-derived cells displayed an upregulated expression of a panel of otic/placodal markers. Strikingly, a subset of these induced progenitor cells displayed key-otic sensory markers, the percentage of which was increased in cultures under Notch inhibition as compared to RA/EGF-treated cultures. Our results show that modulating Notch pathway during in vitro differentiation of hiPSC-derived otic/placodal progenitors is a valuable strategy to promote the expression of human otic sensory lineage genes.
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Affiliation(s)
- Hanae Lahlou
- Aix Marseille Université, CNRS, LNIA UMR 7260, Marseille, France
| | | | - Arnaud Fontbonne
- Aix Marseille Université, CNRS, LNIA UMR 7260, Marseille, France
| | - Emmanuel Nivet
- Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, France
| | - Azel Zine
- Aix Marseille Université, CNRS, LNIA UMR 7260, Marseille, France
- Université de Montpellier, Faculté de Pharmacie, Montpellier, France
- * E-mail: ,
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Abstract
Drug delivery to the inner ear is an ideal method to treat a wide variety of otologic conditions. A broad range of potential applications is just beginning to be explored. New approaches combine principles of inner ear pharmacokinetics with emerging technologies of drug delivery including novel delivery systems, drug-device combinations, and new categories of drugs. Strategies include cell-specific targeting, manipulation of gene expression, local activation following systemic delivery, and use of stem cells, viral vectors, and gene editing systems. Translation of these therapies to the clinic remains challenging given the potential risks of intracochlear and intralabyrinthine trauma, our limited understanding of the etiologies of particular inner ear disorders, and paucity of accurate diagnostic tools at the cellular level. This review provides an overview of future methods, delivery systems, disease targets, and clinical considerations required for translation to clinical medicine.
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Lien S, Dickman JD. Vestibular Injury After Low-Intensity Blast Exposure. Front Neurol 2018; 9:297. [PMID: 29867715 PMCID: PMC5960675 DOI: 10.3389/fneur.2018.00297] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/17/2018] [Indexed: 01/19/2023] Open
Abstract
The increased use of close range explosives has led to a higher incidence of exposure to blast-related head trauma. Exposure to primary blast waves is a significant cause of morbidity and mortality. Active service members and civilians who have experienced blast waves report high rates of vestibular dysfunction, such as vertigo, oscillopsia, imbalance, and dizziness. Accumulating evidence suggests that exposure to blast-wave trauma produces damage to both the peripheral and central vestibular system; similar to previous findings that blast exposure results in damage to auditory receptors. In this study, mice were exposed to a 63 kPa peak blast-wave over pressure and were examined for vestibular receptor damage as well as behavioral assays to identify vestibular dysfunction. We observed perforations to the tympanic membrane in all blast animals. We also observed significant loss of stereocilia on hair cells in the cristae and macule up to 1 month after blast-wave exposure; damage that is likely permanent. Significant reductions in the ability to perform the righting reflex and balance on a rotating rod that lasted several weeks after blast exposure were prominent behavioral effects. We also observed a significant reduction in horizontal vestibuloocular reflex gain and phase lags in the eye movement responses that lasted many weeks following a single blast exposure event. OKN responses were absent immediately following blast exposure, but began to return after several weeks’ recovery. These results show that blast-wave exposure can lead to peripheral vestibular damage (possibly central deficits as well) and provides some insight into causes of vestibular dysfunction in blast-trauma victims.
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Affiliation(s)
- Steven Lien
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - J David Dickman
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States.,Department of Biosciences, Rice University, Houston, TX, United States.,Department of Psychology, Rice University, Houston, TX, United States
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