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Abdelwahed MHAE, Badreldin MH, Ibrahim IH, Zittoon RF, Galhom RA, Mohammed SS, Ashry YM. The potential of bone marrow derived mesenchymal stem cells in treating cisplatin induced sensorineural hearing loss in a guinea pig animal model. Tissue Cell 2025; 93:102703. [PMID: 39756116 DOI: 10.1016/j.tice.2024.102703] [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: 09/27/2024] [Revised: 12/05/2024] [Accepted: 12/21/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Current solutions for SNHL, including hearing aids, cochlear implants, and hearing assistive devices, do not provide consistent results and fail to address the underlying pathology of hair cell and ganglion cell damage. Stem cell therapy is a cornerstone in regenerative medicine. It provides new hope to treat SNHL by replacing/regenerating damaged hair cells and ganglion cells. Mesenchymal stem cells are an interesting choice in stem cell therapy. AIM OF THE WORK Evaluation of bone marrow derived mesenchymal stem cell (BM-MSC) transplantation to improve SNHL management. METHODS An experimental study was conducted using 40 recipient guinea pigs, randomly divided into four groups, along with 4 donor guinea pigs for bone marrow harvesting to isolate BM-MSC. Group I (12 animals) served as the control, receiving neither ototoxic drugs nor stem cell treatment. Group II (12 animals) received intraperitoneal cisplatin (1.5 mg/kg/day for 8 days) to induce sensorineural hearing loss, but no stem cell treatment. Group III (12 animals) received IP cisplatin to induce SNHL, followed by BM-MSC transplantation via round window injection one week later. Groups I, II, and III were euthanized 5 weeks after the last cisplatin injection, and their cochleae were examined using light microscopy, scanning electron microscopy, and fluorescent light microscopy to assess the effect of stem cell transplantation on the recovery of neurosensory tissue in the cochlea after cisplatin treatment. Group IV (4 animals) received IP cisplatin to induce SNHL, followed by transplantation of fluorescein-labeled BM-MSC (FLBM-MSC) via round window injection one week later and were euthanized after one week to study stem cell migration and homing. RESULTS Light Microscopy: Group I exhibited a normal structure in the organ of Corti, spiral ganglion, and stria vascularis. In contrast, Group II demonstrated degeneration in these areas. Group III showed a preserved structure in the organ of Corti, spiral ganglion, and stria vascularis, with statistically significant differences compared to Group II (p < .05). Scanning Electron Microscopy: Group I displayed normal ultrastructure of the organ of Corti, while Group II showed a loss of outer hair cells. Group III demonstrated preserved ultrastructure of the organ of Corti. Fluorescent Light Microscopy: In Group IV, transplanted cells were observed to home into the cochlear lateral wall, organ of Corti, and spiral ganglion. CONCLUSION The study showed that BM-MSCs, delivered via round window injection, can migrate to cochlear regions and protect key structures after cisplatin-induced SNHL in guinea pigs, suggesting their potential as a treatment for SNHL.
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Affiliation(s)
| | | | | | | | - Rania A Galhom
- Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Tissue culture unit, Center of Excellence of Molecular and Cellular Medicine (CEMCM), Suez Canal University, Assistant Professor of Human Anatomy and Embryology, Faculty of Medicine, Galala University, Egypt.
| | - Sally S Mohammed
- Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Yehia Mohamed Ashry
- ENT Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
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Zhang L, Huang PJ, Deng X, Tang J, Zhai Y, Wang T. Physical rehabilitation for sensorineural hearing loss in childhood: Progress and challenges. World J Clin Cases 2025; 13:97847. [PMID: 40051800 PMCID: PMC11612682 DOI: 10.12998/wjcc.v13.i7.97847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 10/23/2024] [Accepted: 11/19/2024] [Indexed: 11/25/2024] Open
Abstract
Early intervention for sensorineural hearing loss (SNHL) in childhood is crucial for auditory and language development. In recent years, innovative auditory stimulation techniques and speech therapy strategies, such as middle ear implants, cochlear implants, auditory brainstem implants, and midbrain implants, have provided new avenues for improving patient outcomes. Additionally, basic research advancements in cell reprogramming and regeneration, stem cell therapy, and targeted drug delivery offer promising approaches to meet the individualized needs of children with SNHL. However, many challenges and unresolved issues remain in the treatment of SNHL. This article comments on the case report, which describes a female pediatric patient with SNHL who underwent foot reflexology which led to the normalization of hearing thresholds. Reflexology is considered to have potential benefits in physical rehabilitation, but its efficacy in hearing restoration requires further scientific validation through rigorous clinical trials and large-scale prospective studies.
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Affiliation(s)
- Lu Zhang
- Department of Pediatrics, Luzhou Maternal and Child Health Hospital, Luzhou 646600, Sichuan Province, China
| | - Pu-Jue Huang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Pediatrics, The First People's Hospital of Longquanyi District, Chengdu 610100, Sichuan Province, China
| | - Xue Deng
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Ministry of Education, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu 610041, Sichuan Province, China
| | - Jiao Tang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Pediatrics, The First People's Hospital of Longquanyi District, Chengdu 610100, Sichuan Province, China
| | - Yang Zhai
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Pediatrics, Chengdu Women’s and Children’s Central Hospital, Chengdu 610000, Sichuan Province, China
| | - Tao Wang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Ministry of Education, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu 610041, Sichuan Province, China
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3
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Xu S, Liu D, Zhang F, Tian Y. Innovative treatment of age-related hearing loss using MSCs and EVs with Apelin. Cell Biol Toxicol 2025; 41:31. [PMID: 39820591 PMCID: PMC11739245 DOI: 10.1007/s10565-025-09988-4] [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: 08/05/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
Utilizing single-cell transcriptome sequencing (scRNA-seq) technology, this study explores the viability of employing mesenchymal stem cells (MSCs) as a therapeutic approach for age-related hearing loss (ARHL). The research demonstrates MSCs' ability to differentiate into inner ear cell subpopulations, particularly hair cells, delivering Apelin via extracellular vesicles (EVs) to promote M2 macrophage polarization. In vitro experiments show reduced inflammation and preservation of hair cell health. In elderly mice, MSCs transplantation leads to hair cell regeneration, restoring auditory function. These findings highlight the regenerative capabilities of MSCs and EV-mediated therapeutic approaches for ARHL.
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Affiliation(s)
- Shengqun Xu
- Ear, Nose, Throat, Head and Neck Surgery Comprehensive Ward, Shengjing Hospital of China Medical University, Shenyang, 110020, China
| | - Dongliang Liu
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Fang Zhang
- Department of Otorhinolaryngology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
| | - Yuan Tian
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Christoffers S, Wichert N, Wiebe E, Torres-Mapa ML, Goblet M, Harre J, Kaiser O, Wahalla MN, Blume H, Heisterkamp A, Warnecke A, Blume C. Blue Light-Induced, Dosed Protein Expression of Active BDNF in Human Cells Using the Optogenetic CRY2/CIB System. Biotechnol J 2024; 19:e202400384. [PMID: 39726067 DOI: 10.1002/biot.202400384] [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: 06/17/2024] [Revised: 11/28/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024]
Abstract
The use of optogenetic tools offers an excellent method for spatially and temporally regulated gene and protein expression in cell therapeutic approaches. This could be useful as a concomitant therapeutic measure, especially in small body compartments such as the inner ear, for example, during cochlea implantation, to enhance neuronal cell survival and function. Here, we used the blue light activatable CRY2/CIB system to induce transcription of brain-derived neurotrophic factor (BDNF) in human cells. Transfection with three plasmids, encoding for the optogenetic system and the target, as well as illumination protocols were optimized with luciferase as a reporter to achieve the highest protein expression in human embryonic kidney cells 293. Illumination was performed either with a light-emitting diode or with a scanning laser setup. The optimized protocols were applied for the production of BDNF. We could demonstrate a 64.7-fold increase of BNDF expression upon light induction compared to the basal level. Light-induced BDNF was biologically active and enhanced survival and neurite growth of spiral ganglion neurons. The optogenetic approach can be transferred to autologous cell systems, such as bone marrow-derived mesenchymal stem cells, and thus represents the first optogenetic neurotrophic therapy for the inner ear.
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Affiliation(s)
- Sina Christoffers
- Institute of Technical Chemistry, Leibniz University Hannover, Hannover, Germany
- Cluster of Excellence Hearing4all, Hannover, Germany
| | - Nina Wichert
- Institute of Technical Chemistry, Leibniz University Hannover, Hannover, Germany
- Cluster of Excellence Hearing4all, Hannover, Germany
| | - Elena Wiebe
- Institute of Technical Chemistry, Leibniz University Hannover, Hannover, Germany
- Cluster of Excellence Hearing4all, Hannover, Germany
| | - Maria Leilani Torres-Mapa
- Cluster of Excellence Hearing4all, Hannover, Germany
- Institute of Quantum Optics, Leibniz University Hannover, Hannover, Germany
| | - Madeleine Goblet
- Department of Otorhinolaryngology, Hannover Medical School, Hannover, Germany
| | - Jennifer Harre
- Cluster of Excellence Hearing4all, Hannover, Germany
- Department of Otorhinolaryngology, Hannover Medical School, Hannover, Germany
| | - Odett Kaiser
- Cluster of Excellence Hearing4all, Hannover, Germany
- Department of Otorhinolaryngology, Hannover Medical School, Hannover, Germany
| | - Marc-Nils Wahalla
- Cluster of Excellence Hearing4all, Hannover, Germany
- Institute of Microelectronic Systems, Leibniz University Hannover, Hannover, Germany
| | - Holger Blume
- Cluster of Excellence Hearing4all, Hannover, Germany
- Institute of Microelectronic Systems, Leibniz University Hannover, Hannover, Germany
| | - Alexander Heisterkamp
- Cluster of Excellence Hearing4all, Hannover, Germany
- Institute of Quantum Optics, Leibniz University Hannover, Hannover, Germany
| | - Athanasia Warnecke
- Cluster of Excellence Hearing4all, Hannover, Germany
- Department of Otorhinolaryngology, Hannover Medical School, Hannover, Germany
| | - Cornelia Blume
- Institute of Technical Chemistry, Leibniz University Hannover, Hannover, Germany
- Cluster of Excellence Hearing4all, Hannover, Germany
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Maniaci A, Briglia M, Allia F, Montalbano G, Romano GL, Zaouali MA, H’mida D, Gagliano C, Malaguarnera R, Lentini M, Graziano ACE, Giurdanella G. The Role of Pericytes in Inner Ear Disorders: A Comprehensive Review. BIOLOGY 2024; 13:802. [PMID: 39452111 PMCID: PMC11504721 DOI: 10.3390/biology13100802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/02/2024] [Accepted: 10/06/2024] [Indexed: 10/26/2024]
Abstract
Inner ear disorders, including sensorineural hearing loss, Meniere's disease, and vestibular neuritis, are prevalent conditions that significantly impact the quality of life. Despite their high incidence, the underlying pathophysiology of these disorders remains elusive, and current treatment options are often inadequate. Emerging evidence suggests that pericytes, a type of vascular mural cell specialized to maintain the integrity and function of the microvasculature, may play a crucial role in the development and progression of inner ear disorders. The pericytes are present in the microvasculature of both the cochlea and the vestibular system, where they regulate blood flow, maintain the blood-labyrinth barrier, facilitate angiogenesis, and provide trophic support to neurons. Understanding their role in inner ear disorders may provide valuable insights into the pathophysiology of these conditions and lead to the development of novel diagnostic and therapeutic strategies, improving the standard of living. This comprehensive review aims to provide a detailed overview of the role of pericytes in inner ear disorders, highlighting the anatomy and physiology in the microvasculature, and analyzing the mechanisms that contribute to the development of the disorders. Furthermore, we explore the potential pericyte-targeted therapies, including antioxidant, anti-inflammatory, and angiogenic approaches, as well as gene therapy strategies.
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Affiliation(s)
- Antonino Maniaci
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
- Department of Surgery, ENT Unit, Asp 7 Ragusa, 97100 Ragusa, Italy
| | - Marilena Briglia
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Fabio Allia
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Giuseppe Montalbano
- Zebrafish Neuromorphology Laboratory, Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy;
| | - Giovanni Luca Romano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Mohamed Amine Zaouali
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Avicenne Street, 5019 Monastir, Tunisia;
| | - Dorra H’mida
- Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, 4021 Sousse, Tunisia;
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Roberta Malaguarnera
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Mario Lentini
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
- Department of Surgery, ENT Unit, Asp 7 Ragusa, 97100 Ragusa, Italy
| | - Adriana Carol Eleonora Graziano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Giovanni Giurdanella
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
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Amiri M, Kaviari MA, Rostaminasab G, Barimani A, Rezakhani L. A novel cell-free therapy using exosomes in the inner ear regeneration. Tissue Cell 2024; 88:102373. [PMID: 38640600 DOI: 10.1016/j.tice.2024.102373] [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: 12/22/2023] [Revised: 03/01/2024] [Accepted: 04/03/2024] [Indexed: 04/21/2024]
Abstract
Cellular and molecular alterations associated with hearing loss are now better understood with advances in molecular biology. These changes indicate the participation of distinct damage and stress pathways that are unlikely to be fully addressed by conventional pharmaceutical treatment. Sensorineural hearing loss is a common and debilitating condition for which comprehensive pharmacologic intervention is not available. The complex and diverse molecular pathology that underlies hearing loss currently limits our ability to intervene with small molecules. The present review focuses on the potential for the use of extracellular vesicles in otology. It examines a variety of inner ear diseases and hearing loss that may be treatable using exosomes (EXOs). The role of EXOs as carriers for the treatment of diseases related to the inner ear as well as EXOs as biomarkers for the recognition of diseases related to the ear is discussed.
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Affiliation(s)
- Masoumeh Amiri
- Faculty of Medicine, Kermanshah University of Medical Science, Kermanshah, Iran
| | - Mohammad Amin Kaviari
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran; Universal Scientific Education and Research Network (USERN) Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gelavizh Rostaminasab
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amir Barimani
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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7
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Fei G, Dandan S, Haiyan W, Shuai Z, Xiaopin S, Yu H, Yi Y, Rong C, Jin H, Xiaoming S, Lei Y. Exogenous neuritin restores auditory following cochlear spiral ganglion neuron denervation of gerbils. Neurosci Res 2024; 200:8-19. [PMID: 37926219 DOI: 10.1016/j.neures.2023.11.001] [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: 07/14/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/07/2023]
Abstract
Spiral ganglion neurons (SGNs) transmit sound signals received by hair cells to the auditory center to produce hearing. The quantity and function are important for maintaining normal hearing function. Limited by the regenerative capacity, SGNs are unable to regenerate spontaneously after injury. Various neurotrophic factors play an important role in the regeneration process. Neuritin is a neurite growth factor that plays an important role in neural plasticity and nerve injury repair. In this study, we used bioinformatics analysis to show that neuritin was negatively correlated with cochlear damage. Then, we aimed to establish a cochlear spiral ganglion-specific sensorineural deafness model in gerbils using ouabain and determine the effects of exogenous neuritin protein in protecting damaged cochlear SGNs and repairing damaged auditory nerve function. The provides a new research strategy and scientific basis for the prevention and treatment of sensorineural deafness caused by the loss of SGNs. We were discovered that neuritin is expressed throughout the development of the gerbil cochlea, primarily in the SGNs and Corti regions. The expression of neuritin was negatively correlated with the sensorineural deafness induced by ouabain. In vitro and in vivo revealed that neuritin significantly maintained the number and arrangement of SGNs and nerve fibers in the damaged cochlea and effectively protected the high-frequency listening function of gerbils.
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Affiliation(s)
- Gui Fei
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832003, PR China.
| | - Song Dandan
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832003, PR China; Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China
| | - Wang Haiyan
- Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China
| | - Zhang Shuai
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832003, PR China
| | - Sun Xiaopin
- Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China
| | - Hong Yu
- Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China
| | - Yang Yi
- Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China
| | - Chen Rong
- Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China
| | - Huang Jin
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832003, PR China.
| | - Song Xiaoming
- Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China.
| | - Yang Lei
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832003, PR China.
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Engert J, Spahn B, Sommerer S, Ehret Kasemo T, Hackenberg S, Rak K, Voelker J. Adult Neurogenesis of the Medial Geniculate Body: In Vitro and Molecular Genetic Analyses Reflect the Neural Stem Cell Capacity of the Rat Auditory Thalamus over Time. Int J Mol Sci 2024; 25:2623. [PMID: 38473870 DOI: 10.3390/ijms25052623] [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: 12/23/2023] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Neural stem cells (NSCs) have been recently identified in the neonatal rat medial geniculate body (MGB). NSCs are characterized by three cardinal features: mitotic self-renewal, formation of progenitors, and differentiation into all neuroectodermal cell lineages. NSCs and the molecular factors affecting them are particularly interesting, as they present a potential target for treating neurologically based hearing disorders. It is unclear whether an NSC niche exists in the rat MGB up to the adult stage and which neurogenic factors are essential during maturation. The rat MGB was examined on postnatal days 8, 12, and 16, and at the adult stadium. The cardinal features of NSCs were detected in MGB cells of all age groups examined by neurosphere, passage, and differentiation assays. In addition, real-time quantitative polymerase chain reaction arrays were used to compare the mRNA levels of 84 genes relevant to NSCs and neurogenesis. In summary, cells of the MGB display the cardinal features of NSCs up to the adult stage with a decreasing NSC potential over time. Neurogenic factors with high importance for MGB neurogenesis were identified on the mRNA level. These findings should contribute to a better understanding of MGB neurogenesis and its regenerative capacity.
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Affiliation(s)
- Jonas Engert
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
| | - Bjoern Spahn
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
| | - Sabine Sommerer
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
| | - Totta Ehret Kasemo
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
| | - Stephan Hackenberg
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
| | - Kristen Rak
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
| | - Johannes Voelker
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany
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9
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Lu J, Wang M, Wang X, Meng Y, Chen F, Zhuang J, Han Y, Wang H, Liu W. A basement membrane extract-based three-dimensional culture system promotes the neuronal differentiation of cochlear Sox10-positive glial cells in vitro. Mater Today Bio 2024; 24:100937. [PMID: 38269057 PMCID: PMC10805941 DOI: 10.1016/j.mtbio.2023.100937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/14/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
Spiral ganglion neurons (SGNs) in the mammalian cochleae are essential for the delivery of acoustic information, and damage to SGNs can lead to permanent sensorineural hearing loss as SGNs are not capable of regeneration. Cochlear glial cells (GCs) might be a potential source for SGN regeneration, but the neuronal differentiation ability of GCs is limited and its properties are not clear yet. Here, we characterized the cochlear Sox10-positive (Sox10+) GCs as a neural progenitor population and developed a basement membrane extract-based three-dimensional (BME-3D) culture system to promote its neuronal generation capacity in vitro. Firstly, the purified Sox10+ GCs, isolated from Sox10-creER/tdTomato mice via flow cytometry, were able to form neurospheres after being cultured in the traditional suspension culture system, while significantly more neurospheres were found and the expression of stem cell-related genes was upregulated in the BME-3D culture group. Next, the BME-3D culture system promoted the neuronal differentiation ability of Sox10+ GCs, as evidenced by the increased number, neurite outgrowth, area of growth cones, and synapse density as well as the promoted excitability of newly induced neurons. Notably, the BME-3D culture system also intensified the reinnervation of newly generated neurons with HCs and protected the neurospheres and derived-neurons against cisplatin-induced damage. Finally, transcriptome sequencing analysis was performed to identify the characteristics of the differentiated neurons. These findings suggest that the BME-3D culture system considerably promotes the proliferation capacity and neuronal differentiation efficiency of Sox10+ GCs in vitro, thus providing a possible strategy for the SGN regeneration study.
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Affiliation(s)
- Junze Lu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Man Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Xue Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Yu Meng
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Fang Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Jinzhu Zhuang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Yuechen Han
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Haibo Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
| | - Wenwen Liu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China
- Shandong Institute of Otorhinolaryngology, Jinan, 250022, China
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10
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Cumpata AJ, Labusca L, Radulescu LM. Stem Cell-Based Therapies for Auditory Hair Cell Regeneration in the Treatment of Hearing Loss. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:15-28. [PMID: 37440318 DOI: 10.1089/ten.teb.2023.0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/15/2023]
Abstract
The incidence and prevalence of hearing loss is increasing globally at an accelerated pace. Hair cells represent the sensory receptors of auditory and vestibular systems. Hair cell absence, loss or degeneration due to congenital diseases, trauma, toxicity, infection or advancing age, results in disabling hearing loss. Regenerative medicine approaches consisting in stem cell-based hair cell rescue or regeneration, gene therapy, as well as cell and tissue engineering are expected to dramatically improve the therapeutic arsenal available for addressing hearing loss. Current strategies that are using different stem cell types to rescue or to induce hair cell proliferation and regeneration are presented. Gene and cell therapy methods that modulates transdifferentiation of surrounding cell types into hair cells are presented, together with their specific advantages and limitations. Several modalities for improving therapeutic targeting to the inner ear such as nanoparticle-mediated cell and gene delivery are introduced. Further steps in building more relevant high-throughput models for testing novel drugs and advanced therapies are proposed as a modality to accelerate translation to clinical settings.
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Affiliation(s)
| | - Luminita Labusca
- Orthopedics and Traumatology Clinic, Emergency Hospital Saint Spiridon, Iasi, Romania
- Magnetic Materials and Sensors, National Institute of Research and Development in Technical Physics, Iasi, Romania
| | - Luminita Mihaela Radulescu
- Doctoral School, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
- ENT Clinic Department, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
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11
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Chang SY, Kim E, Carpena NT, Lee JH, Kim DH, Lee MY. Photobiomodulation Can Enhance Stem Cell Viability in Cochlea with Auditory Neuropathy but Does Not Restore Hearing. Stem Cells Int 2023; 2023:6845571. [PMID: 38020205 PMCID: PMC10665102 DOI: 10.1155/2023/6845571] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/15/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Sensorineural hearing loss is very difficult to treat. Currently, one of the techniques used for hearing rehabilitation is a cochlear implant that can transform sound into electrical signals instead of inner ear hair cells. However, the prognosis remains very poor if sufficient auditory nerve cells are not secured. In this study, the effect of mouse embryonic stem cells (mESC) and photobiomodulation (PBM) combined treatment on auditory function and auditory nerve cells in a secondary neuropathy animal model was investigated. To confirm the engraftment of stem cells in vitro, cochlear explants were treated with kanamycin (KM) to mimic nerve damage and then cocultured with GFP-mESC. GFP-mESCs were observed to have attached and integrated into the explanted samples. An animal model for secondary neurodegeneration was achieved by KM treatment and was treated by a combination therapy of GFP-mESC and NIR-PBM at 8 weeks of KM treatment. Hearing recovery by functional testing using auditory brain stem response (ABR) and eABR was measured as well as morphological changes and epifluorescence analysis were conducted after 2 weeks of combination therapy. KM treatment elevated the hearing threshold at 70-80 dB and even after the combination treatment with GFP-mESC and PBM was applied, the auditory function was not restored. In addition, the stem cells transplanted into cochlea has exponentially increased due to PBM treatment although did not produce any malignancy. This study confirmed that the combined treatment with mESC and PBM could not improve hearing or increase the response of the auditory nerve. Nevertheless, it is noteworthy in this study that the cells are distributed in most cochlear tissues and the proliferation of stem cells was very active in animals irradiated with PBM compared to other groups wherein the stem cells had disappeared immediately after transplantation or existed for only a short period of time.
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Affiliation(s)
- So-Young Chang
- Beckman Laser Institute Korea, Dankook University, Cheonan 31116, Republic of Korea
| | - Eunjeong Kim
- Department of Biological Science, College of Science & Technology, Dankook University, Cheonan 31116, Republic of Korea
| | - Nathaniel T. Carpena
- Department of Otolaryngology-Head & Neck Surgery, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Jae-Hun Lee
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea
| | | | - Min Young Lee
- Beckman Laser Institute Korea, Dankook University, Cheonan 31116, Republic of Korea
- Department of Otolaryngology-Head & Neck Surgery, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea
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12
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Petit C, Bonnet C, Safieddine S. Deafness: from genetic architecture to gene therapy. Nat Rev Genet 2023; 24:665-686. [PMID: 37173518 DOI: 10.1038/s41576-023-00597-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2023] [Indexed: 05/15/2023]
Abstract
Progress in deciphering the genetic architecture of human sensorineural hearing impairment (SNHI) or loss, and multidisciplinary studies of mouse models, have led to the elucidation of the molecular mechanisms underlying auditory system function, primarily in the cochlea, the mammalian hearing organ. These studies have provided unparalleled insights into the pathophysiological processes involved in SNHI, paving the way for the development of inner-ear gene therapy based on gene replacement, gene augmentation or gene editing. The application of these approaches in preclinical studies over the past decade has highlighted key translational opportunities and challenges for achieving effective, safe and sustained inner-ear gene therapy to prevent or cure monogenic forms of SNHI and associated balance disorders.
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Affiliation(s)
- Christine Petit
- Institut Pasteur, Université Paris Cité, Inserm, Institut de l'Audition, F-75012, Paris, France.
- Collège de France, F-75005, Paris, France.
| | - Crystel Bonnet
- Institut Pasteur, Université Paris Cité, Inserm, Institut de l'Audition, F-75012, Paris, France
| | - Saaïd Safieddine
- Institut Pasteur, Université Paris Cité, Inserm, Institut de l'Audition, F-75012, Paris, France
- Centre National de la Recherche Scientifique, F-75016, Paris, France
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13
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Starovoyt A, Quirk BC, Putzeys T, Kerckhofs G, Nuyts J, Wouters J, McLaughlin RA, Verhaert N. An optically-guided cochlear implant sheath for real-time monitoring of electrode insertion into the human cochlea. Sci Rep 2022; 12:19234. [PMID: 36357503 PMCID: PMC9649659 DOI: 10.1038/s41598-022-23653-4] [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: 08/01/2022] [Accepted: 11/03/2022] [Indexed: 11/12/2022] Open
Abstract
In cochlear implant surgery, insertion of perimodiolar electrode arrays into the scala tympani can be complicated by trauma or even accidental translocation of the electrode array within the cochlea. In patients with partial hearing loss, cochlear trauma can not only negatively affect implant performance, but also reduce residual hearing function. These events have been related to suboptimal positioning of the cochlear implant electrode array with respect to critical cochlear walls of the scala tympani (modiolar wall, osseous spiral lamina and basilar membrane). Currently, the position of the electrode array in relation to these walls cannot be assessed during the insertion and the surgeon depends on tactile feedback, which is unreliable and often comes too late. This study presents an image-guided cochlear implant device with an integrated, fiber-optic imaging probe that provides real-time feedback using optical coherence tomography during insertion into the human cochlea. This novel device enables the surgeon to accurately detect and identify the cochlear walls ahead and to adjust the insertion trajectory, avoiding collision and trauma. The functionality of this prototype has been demonstrated in a series of insertion experiments, conducted by experienced cochlear implant surgeons on fresh-frozen human cadaveric cochleae.
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Affiliation(s)
- Anastasiya Starovoyt
- grid.5596.f0000 0001 0668 7884Department of Neurosciences, ExpORL, KU Leuven, 3000 Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium
| | - Bryden C. Quirk
- grid.1010.00000 0004 1936 7304Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005 Australia ,grid.1010.00000 0004 1936 7304Institute for Photonics and Advanced Sensing, The University of Adelaide, Adelaide, SA 5005 Australia
| | - Tristan Putzeys
- grid.5596.f0000 0001 0668 7884Department of Neurosciences, ExpORL, KU Leuven, 3000 Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for Soft Matter and Biophysics, Department of Physics and Astronomy, KU Leuven, 3000 Leuven, Belgium
| | - Greet Kerckhofs
- grid.7942.80000 0001 2294 713XBiomechanics Laboratory, Institute of Mechanics, Materials, and Civil Engineering, UCLouvain, 1348 Louvain-La-Neuve, Belgium ,grid.5596.f0000 0001 0668 7884Department of Materials Science and Engineering, KU Leuven, 3000 Leuven, Belgium ,grid.7942.80000 0001 2294 713XInstitute of Experimental and Clinical Research, UCLouvain, 1200 Woluwé-Saint-Lambert, Belgium ,grid.5596.f0000 0001 0668 7884Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium
| | - Johan Nuyts
- grid.5596.f0000 0001 0668 7884Department of Imaging and Pathology, Division of Nuclear Medicine, KU Leuven, 3000 Leuven, Belgium ,Nuclear Medicine and Molecular Imaging, Medical Imaging Research Center, 3000 Leuven, Belgium
| | - Jan Wouters
- grid.5596.f0000 0001 0668 7884Department of Neurosciences, ExpORL, KU Leuven, 3000 Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium
| | - Robert A. McLaughlin
- grid.1010.00000 0004 1936 7304Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005 Australia ,grid.1010.00000 0004 1936 7304Institute for Photonics and Advanced Sensing, The University of Adelaide, Adelaide, SA 5005 Australia ,grid.1012.20000 0004 1936 7910School of Engineering, University of Western Australia, Perth, WA 6009 Australia
| | - Nicolas Verhaert
- grid.5596.f0000 0001 0668 7884Department of Neurosciences, ExpORL, KU Leuven, 3000 Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium ,grid.410569.f0000 0004 0626 3338Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals of Leuven, 3000 Leuven, Belgium
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14
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Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene Ther 2022; 29:479-497. [PMID: 33633356 DOI: 10.1038/s41434-021-00240-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/18/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss (HL), which accounts for approximately 2-5% of all patients with congenital hearing loss. WS is classified into four subtypes depending on the clinical phenotypes. Currently, pathogenic mutations of PAX3, MITF, SOX10, EDN3, EDNRB or SNAI2 are associated with different subtypes of WS. Although supportive techniques like hearing aids, cochlear implants, or other assistive listening devices can alleviate the HL symptom, there is no cure for WS to date. Recently major progress has been achieved in preclinical studies of genetic HL in animal models, including gene delivery and stem cell replacement therapies. This review focuses on the current understandings of pathogenic mechanisms and potential biological therapeutic approaches for HL in WS, providing strategies and directions for implementing WS biological therapies, as well as possible problems to be faced, in the future.
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15
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Blebea CM, Ujvary LP, Necula V, Dindelegan MG, Perde-Schrepler M, Stamate MC, Cosgarea M, Maniu AA. Current Concepts and Future Trends in Increasing the Benefits of Cochlear Implantation: A Narrative Review. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:747. [PMID: 35744010 PMCID: PMC9229893 DOI: 10.3390/medicina58060747] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/25/2022] [Accepted: 05/29/2022] [Indexed: 01/29/2023]
Abstract
Hearing loss is the most common neurosensory disorder, and with the constant increase in etiological factors, combined with early detection protocols, numbers will continue to rise. Cochlear implantation has become the gold standard for patients with severe hearing loss, and interest has shifted from implantation principles to the preservation of residual hearing following the procedure itself. As the audiological criteria for cochlear implant eligibility have expanded to include patients with good residual hearing, more attention is focused on complementary development of otoprotective agents, electrode design, and surgical approaches. The focus of this review is current aspects of preserving residual hearing through a summary of recent trends regarding surgical and pharmacological fundamentals. Subsequently, the assessment of new pharmacological options, novel bioactive molecules (neurotrophins, growth factors, etc.), nanoparticles, stem cells, and gene therapy are discussed.
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Affiliation(s)
- Cristina Maria Blebea
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
| | - Laszlo Peter Ujvary
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
| | - Violeta Necula
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
- County Clinical Emergency Hospital Cluj, 400347 Cluj Napoca, Romania
| | - Maximilian George Dindelegan
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
| | | | - Mirela Cristina Stamate
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
| | - Marcel Cosgarea
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
| | - Alma Aurelia Maniu
- Department of Otorhinolaryngology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania; (C.M.B.); (V.N.); (M.G.D.); (M.C.S.); (M.C.); (A.A.M.)
- County Clinical Emergency Hospital Cluj, 400347 Cluj Napoca, Romania
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16
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Liu SS, Yang R. Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities. Front Neurosci 2022; 16:867453. [PMID: 35685768 PMCID: PMC9170894 DOI: 10.3389/fnins.2022.867453] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 05/02/2022] [Indexed: 12/20/2022] Open
Abstract
Most therapies for treating sensorineural hearing loss are challenged by the delivery across multiple tissue barriers to the hard-to-access anatomical location of the inner ear. In this review, we will provide a recent update on various pharmacotherapy, gene therapy, and cell therapy approaches used in clinical and preclinical studies for the treatment of sensorineural hearing loss and approaches taken to overcome the drug delivery barriers in the ear. Small-molecule drugs for pharmacotherapy can be delivered via systemic or local delivery, where the blood-labyrinth barrier hinders the former and tissue barriers including the tympanic membrane, the round window membrane, and/or the oval window hinder the latter. Meanwhile, gene and cell therapies often require targeted delivery to the cochlea, which is currently achieved via intra-cochlear or intra-labyrinthine injection. To improve the stability of the biomacromolecules during treatment, e.g., RNAs, DNAs, proteins, additional packing vehicles are often required. To address the diverse range of biological barriers involved in inner ear drug delivery, each class of therapy and the intended therapeutic cargoes will be discussed in this review, in the context of delivery routes commonly used, delivery vehicles if required (e.g., viral and non-viral nanocarriers), and other strategies to improve drug permeation and sustained release (e.g., hydrogel, nanocarriers, permeation enhancers, and microfluidic systems). Overall, this review aims to capture the important advancements and key steps in the development of inner ear therapies and delivery strategies over the past two decades for the treatment and prophylaxis of sensorineural hearing loss.
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Affiliation(s)
- Sophie S. Liu
- Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, United States
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
| | - Rong Yang
- Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, United States
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
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17
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Zhang YL, Kang M, Wu JC, Xie MY, Xue RY, Tang Q, Yang H, Li LC. Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells. Bioengineered 2022; 13:6729-6739. [PMID: 35246011 PMCID: PMC8974106 DOI: 10.1080/21655979.2022.2045835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The loss of inner ear hair cells leads to irreversible acoustic injury in mammals, and regeneration of inner ear hair cells to restore hearing loss is challenging. ATOH1 is a key gene in the development and regeneration of hair cells. Small activating RNAs (saRNAs) can target a gene to specifically upregulate its expression. This study aimed to explore whether small activating RNAs could induce the differentiation of human adipose-derived mesenchymal stem cells into hair cell-like cells with a combination of growth factors in vitro and thus provide a new strategy for hair cell regeneration and the treatment of sensorineural hearing loss. Fifteen small activating RNAs targeting the human ATOH1 gene were designed and screened in 293 T and human adipose-derived mesenchymal stem cells, and 3 of these candidates were found to be capable of effectively and stably activating ATOH1 gene expression. The selected small activating RNAs were then transfected into hair cell progenitor cells, and hair cell markers were examined 10 days after transfection. After transfection of the selected small activating RNAs, the expression of the characteristic markers of inner ear hair cells, POU class 4 homeobox 3 (POU4F3) and myosin VIIA (MYO7A), was detected. Human adipose-derived mesenchymal stem cells have the potential to differentiate into human hair cell progenitor cells. In vitro, small activating RNAs were able to induce the differentiation of hair cell progenitor cells into hair cell-like cells. Therefore, RNA activation technology has the potential to provide a new strategy for the regeneration of hair cells.
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Affiliation(s)
- Yong-Li Zhang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Moorim Kang
- Ractigen Therapeutics, Nantong, Jiangsu, China
| | | | - Meng-Yao Xie
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Ruo-Yan Xue
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Qi Tang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Hua Yang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Long-Cheng Li
- Ractigen Therapeutics, Nantong, Jiangsu, China.,Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
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18
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Manousiouthakis E, Park J, Hardy JG, Lee JY, Schmidt CE. Towards the translation of electroconductive organic materials for regeneration of neural tissues. Acta Biomater 2022; 139:22-42. [PMID: 34339871 DOI: 10.1016/j.actbio.2021.07.065] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/23/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022]
Abstract
Carbon-based conductive and electroactive materials (e.g., derivatives of graphene, fullerenes, polypyrrole, polythiophene, polyaniline) have been studied since the 1970s for use in a broad range of applications. These materials have electrical properties comparable to those of commonly used metals, while providing other benefits such as flexibility in processing and modification with biologics (e.g., cells, biomolecules), to yield electroactive materials with biomimetic mechanical and chemical properties. In this review, we focus on the uses of these electroconductive materials in the context of the central and peripheral nervous system, specifically recent studies in the peripheral nerve, spinal cord, brain, eye, and ear. We also highlight in vivo studies and clinical trials, as well as a snapshot of emerging classes of electroconductive materials (e.g., biodegradable materials). We believe such specialized electrically conductive biomaterials will clinically impact the field of tissue regeneration in the foreseeable future. STATEMENT OF SIGNIFICANCE: This review addresses the use of conductive and electroactive materials for neural tissue regeneration, which is of significant interest to a broad readership, and of particular relevance to the growing community of scientists, engineers and clinicians in academia and industry who develop novel medical devices for tissue engineering and regenerative medicine. The review covers the materials that may be employed (primarily focusing on derivatives of fullerenes, graphene and conjugated polymers) and techniques used to analyze materials composed thereof, followed by sections on the application of these materials to nervous tissues (i.e., peripheral nerve, spinal cord, brain, optical, and auditory tissues) throughout the body.
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Affiliation(s)
- Eleana Manousiouthakis
- Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville 32611, FL, United States
| | - Junggeon Park
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
| | - John G Hardy
- Department of Chemistry, Lancaster University, Lancaster LA1 4YB, United Kingdom; Materials Science Institute, Lancaster University, Lancaster LA1 4YB, United Kingdom.
| | - Jae Young Lee
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
| | - Christine E Schmidt
- Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville 32611, FL, United States.
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19
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Li M, Mu Y, Cai H, Wu H, Ding Y. Application of New Materials in Auditory Disease Treatment. Front Cell Neurosci 2022; 15:831591. [PMID: 35173583 PMCID: PMC8841849 DOI: 10.3389/fncel.2021.831591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 12/22/2021] [Indexed: 11/16/2022] Open
Abstract
Auditory diseases are disabling public health problems that afflict a significant number of people worldwide, and they remain largely incurable until now. Driven by continuous innovation in the fields of chemistry, physics, and materials science, novel materials that can be applied to hearing diseases are constantly emerging. In contrast to conventional materials, new materials are easily accessible, inexpensive, non-invasive, with better acoustic therapy effects and weaker immune rejection after implantation. When new materials are used to treat auditory diseases, the wound healing, infection prevention, disease recurrence, hair cell regeneration, functional recovery, and other aspects have been significantly improved. Despite these advances, clinical success has been limited, largely due to issues regarding a lack of effectiveness and safety. With ever-developing scientific research, more novel materials will be facilitated into clinical use in the future.
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20
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Warnecke A, Harre J, Shew M, Mellott AJ, Majewski I, Durisin M, Staecker H. Successful Treatment of Noise-Induced Hearing Loss by Mesenchymal Stromal Cells: An RNAseq Analysis of Protective/Repair Pathways. Front Cell Neurosci 2021; 15:656930. [PMID: 34887728 PMCID: PMC8650824 DOI: 10.3389/fncel.2021.656930] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are an adult derived stem cell-like population that has been shown to mediate repair in a wide range of degenerative disorders. The protective effects of MSCs are mainly mediated by the release of growth factors and cytokines thereby modulating the diseased environment and the immune system. Within the inner ear, MSCs have been shown protective against tissue damage induced by sound and a variety of ototoxins. To better understand the mechanism of action of MSCs in the inner ear, mice were exposed to narrow band noise. After exposure, MSCs derived from human umbilical cord Wharton's jelly were injected into the perilymph. Controls consisted of mice exposed to sound trauma only. Forty-eight hours post-cell delivery, total RNA was extracted from the cochlea and RNAseq performed to evaluate the gene expression induced by the cell therapy. Changes in gene expression were grouped together based on gene ontology classification. A separate cohort of animals was treated in a similar fashion and allowed to survive for 2 weeks post-cell therapy and hearing outcomes determined. Treatment with MSCs after severe sound trauma induced a moderate hearing protective effect. MSC treatment resulted in an up-regulation of genes related to immune modulation, hypoxia response, mitochondrial function and regulation of apoptosis. There was a down-regulation of genes related to synaptic remodeling, calcium homeostasis and the extracellular matrix. Application of MSCs may provide a novel approach to treating sound trauma induced hearing loss and may aid in the identification of novel strategies to protect hearing.
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Affiliation(s)
- Athanasia Warnecke
- Clinic for Otolaryngology–Head & Neck Surgery, Hanover Medical School, Hanover, Germany
- Cluster of Excellence “Hearing4all” of the German Research Foundation (EXC 2177/1), Oldenburg, Germany
| | - Jennifer Harre
- Clinic for Otolaryngology–Head & Neck Surgery, Hanover Medical School, Hanover, Germany
- Cluster of Excellence “Hearing4all” of the German Research Foundation (EXC 2177/1), Oldenburg, Germany
| | - Matthew Shew
- Department of Otolaryngology–Head & Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | | | - Igor Majewski
- Clinic for Otolaryngology–Head & Neck Surgery, Hanover Medical School, Hanover, Germany
| | - Martin Durisin
- Clinic for Otolaryngology–Head & Neck Surgery, Hanover Medical School, Hanover, Germany
| | - Hinrich Staecker
- Department of Otolaryngology–Head & Neck Surgery, University of Kansas School of Medicine, Kansas City, KS, United States
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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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22
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MECOM promotes supporting cell proliferation and differentiation in cochlea. J Otol 2021; 17:59-66. [PMID: 35949554 PMCID: PMC9349018 DOI: 10.1016/j.joto.2021.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022] Open
Abstract
Permanent damage to hair cells (HCs) is the leading cause of sensory deafness. Supporting cells (SCs) are essential in the restoration of hearing in mammals because they can proliferate and differentiate to HCs. MDS1 and EVI1 complex locus (MECOM) is vital in early development and cell differentiation and regulates the TGF-β signaling pathway to adapt to pathophysiological events, such as hematopoietic proliferation, differentiation and cells death. In addition, MECOM plays an essential role in neurogenesis and craniofacial development. However, the role of MECOM in the development of cochlea and its way to regulate related signaling are not fully understood. To address this problem, this study examined the expression of MECOM during the development of cochlea and observed a significant increase of MECOM at the key point of auditory epithelial morphogenesis, indicating that MECOM may have a vital function in the formation of cochlea and regeneration of HCs. Meanwhile, we tried to explore the possible effect and potential mechanism of MECOM in SC proliferation and HC regeneration. Findings from this study indicate that overexpression of MECOM markedly increases the proliferation of SCs in the inner ear, and the expression of Smad3 and Cdkn2b related to TGF signaling is significantly down-regulated, corresponding to the overexpression of MECOM. Collectively, these data may provide an explanation of the vital function of MECOM in SC proliferation and trans-differentiation into HCs, as well as its regulation. The interaction between MECOM, Wnt, Notch and the TGF-β signaling may provide a feasible approach to induce the regeneration of HCs.
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23
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Kaboodkhani R, Mehrabani D, Karimi-Busheri F. Achievements and Challenges in Transplantation of Mesenchymal Stem Cells in Otorhinolaryngology. J Clin Med 2021; 10:2940. [PMID: 34209041 PMCID: PMC8267672 DOI: 10.3390/jcm10132940] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
Otorhinolaryngology enrolls head and neck surgery in various tissues such as ear, nose, and throat (ENT) that govern different activities such as hearing, breathing, smelling, production of vocal sounds, the balance, deglutition, facial animation, air filtration and humidification, and articulation during speech, while absence of these functions can lead to high morbidity and even mortality. Conventional therapies for head and neck damaged tissues include grafts, transplants, and artificial materials, but grafts have limited availability and cause morbidity in the donor site. To improve these limitations, regenerative medicine, as a novel and rapidly growing field, has opened a new therapeutic window in otorhinolaryngology by using cell transplantation to target the healing and replacement of injured tissues. There is a high risk of rejection and tumor formation for transplantation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs); mesenchymal stem cells (MSCs) lack these drawbacks. They have easy expansion and antiapoptotic properties with a wide range of healing and aesthetic functions that make them a novel candidate in otorhinolaryngology for craniofacial defects and diseases and hold immense promise for bone tissue healing; even the tissue sources and types of MSCs, the method of cell introduction and their preparation quality can influence the final outcome in the injured tissue. In this review, we demonstrated the anti-inflammatory and immunomodulatory properties of MSCs, from different sources, to be safely used for cell-based therapies in otorhinolaryngology, while their achievements and challenges have been described too.
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Affiliation(s)
- Reza Kaboodkhani
- Otorhinolaryngology Research Center, Department of Otorhinolaryngology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71936-36981, Iran;
| | - Davood Mehrabani
- Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz 71987-74731, Iran
- Comparative and Experimental Medicine Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran
- Li Ka Shing Center for Health Research and Innovation, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Feridoun Karimi-Busheri
- Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, AB T6G 1Z2, Canada
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