167 results on '"Sensory progenitor cells"'
Search Results
2. Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells
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Hanae Lahlou, Emmanuel Nivet, Alejandra Lopez-Juarez, Arnaud Fontbonne, Said Assou, and Azel Zine
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human otic progenitor cells ,human induced pluripotent cells ,otic development ,embryonic hair cells ,in vitro differentiation ,transcriptome (RNA-seq) ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Age-related neurosensory deficit of the inner ear is mostly due to a loss of hair cells (HCs). Development of stem cell-based therapy requires a better understanding of factors and signals that drive stem cells into otic sensory progenitor cells (OSPCs) to replace lost HCs. Human induced pluripotent stem cells (hiPSCs) theoretically represent an unlimited supply for the generation of human OSPCs in vitro. In this study, we developed a monolayer-based differentiation system to generate an enriched population of OSPCs via a stepwise differentiation of hiPSCs. Gene and protein expression analyses revealed the efficient induction of a comprehensive panel of otic/placodal and late otic markers over the course of the differentiation. Furthermore, whole transcriptome analysis confirmed a developmental path of OSPC differentiation from hiPSCs. We found that modulation of WNT and transforming growth factor-β (TGF-β) signaling combined with fibroblast growth factor 3 (FGF3) and FGF10 treatment over a 6-day period drives the expression of early otic/placodal markers followed by late otic sensory markers within 13 days, indicative of a differentiation into embryonic-like HCs. In summary, we report a rapid and efficient strategy to generate an enriched population of OSPCs from hiPSCs, thereby establishing the value of this approach for disease modeling and cell-based therapies of the inner ear.
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- 2018
- Full Text
- View/download PDF
3. The crosstalk between the Notch, Wnt, and SHH signaling pathways in regulating the proliferation and regeneration of sensory progenitor cells in the mouse cochlea
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Liping Zhao, Huawei Li, Wen Li, Luo Guo, Jingfang Wu, and Shan Sun
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0301 basic medicine ,Genetically modified mouse ,Histology ,animal structures ,Cell regeneration ,Pathology and Forensic Medicine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Conditional gene knockout ,Animals ,Hedgehog Proteins ,Sonic hedgehog ,Progenitor cell ,Cells, Cultured ,Cell Proliferation ,biology ,Receptors, Notch ,Cell growth ,Regeneration (biology) ,Stem Cells ,Sensory progenitor cells ,Wnt signaling pathway ,Regular Article ,Cell Biology ,Ototoxicity ,Cell biology ,Cochlea ,Mice, Inbred C57BL ,Wnt Proteins ,030104 developmental biology ,embryonic structures ,biology.protein ,Signal pathway ,sense organs ,Signal transduction ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Sensory hair cells (HCs) are highly susceptible to damage by noise, ototoxic drugs, and aging. Although HCs cannot be spontaneously regenerated in adult mammals, previous studies have shown that signaling pathways are involved in HC regeneration in the damaged mouse cochlea. Here, we used a Notch antagonist (DAPT), a Wnt agonist (QS11), and recombinant Sonic hedgehog (SHH) protein to investigate their concerted actions underlying HC regeneration in the mouse cochlea after neomycin-induced damage both in vivo and in vitro. With DAPT, the numbers of HCs increased, and supporting cell (SC) proliferation was seen in both the intact and damaged cochlear sensory epithelia, while these numbers were unchanged in the presence of QS11. When simultaneously treated with DAPT and QS11, the number of HCs increased dramatically, and much greater SC proliferation was seen in the cochlear epithelium. In transgenic mice with both Notch1 conditional knockout and β-catenin over-expression, cochlear SC proliferation and HC regeneration were more obvious than in either Notch1 knockout or β-catenin over-expressing mice separately. When cochleae were treated with DAPT, QS11, and SHH together, SC proliferation was even greater, and this proliferation was seen in both the HC region and the greater epithelial ridge. High-throughput RNA sequencing was used to identify the differentially expressed genes between all groups, and the results showed that the SHH and Wnt signaling pathways are involved in SC proliferation. Our study suggests that co-regulation of the Notch, Wnt, and SHH signaling pathways promotes extensive cell proliferation and regeneration in the mouse cochlea.
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- 2020
4. Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells.
- Author
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Lahlou H, Nivet E, Lopez-Juarez A, Fontbonne A, Assou S, and Zine A
- Abstract
Age-related neurosensory deficit of the inner ear is mostly due to a loss of hair cells (HCs). Development of stem cell-based therapy requires a better understanding of factors and signals that drive stem cells into otic sensory progenitor cells (OSPCs) to replace lost HCs. Human induced pluripotent stem cells (hiPSCs) theoretically represent an unlimited supply for the generation of human OSPCs in vitro . In this study, we developed a monolayer-based differentiation system to generate an enriched population of OSPCs via a stepwise differentiation of hiPSCs. Gene and protein expression analyses revealed the efficient induction of a comprehensive panel of otic/placodal and late otic markers over the course of the differentiation. Furthermore, whole transcriptome analysis confirmed a developmental path of OSPC differentiation from hiPSCs. We found that modulation of WNT and transforming growth factor-β (TGF-β) signaling combined with fibroblast growth factor 3 (FGF3) and FGF10 treatment over a 6-day period drives the expression of early otic/placodal markers followed by late otic sensory markers within 13 days, indicative of a differentiation into embryonic-like HCs. In summary, we report a rapid and efficient strategy to generate an enriched population of OSPCs from hiPSCs, thereby establishing the value of this approach for disease modeling and cell-based therapies of the inner ear.
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- 2018
- Full Text
- View/download PDF
5. Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells
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Alejandra Lopez-Juarez, Hanae Lahlou, Azel Zine, Arnaud Fontbonne, Said Assou, Emmanuel Nivet, Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was funded by the European Community’s Seventh Framework Programme under grant agreement No. 603029 (Project OTOSTEM). ‘‘La Fondation Pour l’Audition’’ (Paris,France) provided Ph.D. fellowship to HL., European Project: 603029,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,OTOSTEM(2013), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
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0301 basic medicine ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Population ,embryonic hair cells ,Biology ,Fibroblast growth factor ,lcsh:RC321-571 ,Transcriptome ,otic development ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Progenitor cell ,Induced pluripotent stem cell ,education ,Molecular Biology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,human induced pluripotent cells ,education.field_of_study ,FGF10 ,transcriptome (RNA-seq) ,Wnt signaling pathway ,human otic progenitor cells ,Cell biology ,030104 developmental biology ,in vitro differentiation ,sense organs ,Stem cell ,Neuroscience - Abstract
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306956/pdf/fnmol-11-00452.pdf; International audience; Age-related neurosensory deficit of the inner ear is mostly due to a loss of hair cells (HCs). Development of stem cell-based therapy requires a better understanding of factors and signals that drive stem cells into otic sensory progenitor cells (OSPCs) to replace lost HCs. Human induced pluripotent stem cells (hiPSCs) theoretically represent an unlimited supply for the generation of human OSPCs in vitro. In this study, we developed a monolayer-based differentiation system to generate an enriched population of OSPCs via a stepwise differentiation of hiPSCs. Gene and protein expression analyses revealed the efficient induction of a comprehensive panel of otic/placodal and late otic markers over the course of the differentiation. Furthermore, whole transcriptome analysis confirmed a developmental path of OSPC differentiation from hiPSCs. We found that modulation of WNT and transforming growth factor-β (TGF-β) signaling combined with fibroblast growth factor 3 (FGF3) and FGF10 treatment over a 6-day period drives the expression of early otic/placodal markers followed by late otic sensory markers within 13 days, indicative of a differentiation into embryonic-like HCs. In summary, we report a rapid and efficient strategy to generate an enriched population of OSPCs from hiPSCs, thereby establishing the value of this approach for disease modeling and cell-based therapies of the inner ear.
- Published
- 2018
6. New Pluripotent Stem Cells Data Have Been Reported by Researchers at Aix-Marseille University (Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells)
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Stem cells ,Stem cell research ,Stem cell transplantation ,Anopheles ,Somatotropin ,Editors ,Biological sciences ,Health - Abstract
2019 JAN 22 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- Investigators publish new report on Stem Cell Research - Pluripotent Stem Cells. According to [...]
- Published
- 2019
7. FGF signaling: diverse roles during cochlear development
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Sung Ho Huh and Michael Ebeid
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0301 basic medicine ,Ectoderm ,Biology ,Hair cells ,Fibroblast growth factor ,Biochemistry ,FGF signaling ,03 medical and health sciences ,0302 clinical medicine ,Utricle ,Morphogenesis ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Inner ear ,Molecular Biology ,Cochlea ,Sensory progenitor cells ,Wnt signaling pathway ,Cell Differentiation ,Inner ear development ,General Medicine ,Anatomy ,Invited Mini Review ,Cell biology ,Fibroblast Growth Factors ,030104 developmental biology ,medicine.anatomical_structure ,Organ of Corti ,sense organs ,Saccule ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Mammalian inner ear comprises of six sensory organs; cochlea, utricle, saccule, and three semicircular canals. The cochlea contains sensory epithelium known as the organ of Corti which senses sound through mechanosensory hair cells. Mammalian inner ear undergoes series of morphogenesis during development beginning thickening of ectoderm nearby hindbrain. These events require tight regulation of multiple signaling cascades including FGF, Wnt, Notch and Bmp signaling. In this review, we will discuss the role of newly emerging signaling, FGF signaling, for its roles required for cochlear development. [BMB Reports 2017; 50(10): 487-495].
- Published
- 2017
8. Satellite glial cells from adult DRG dedifferentiate in vitro and can be reprogrammed into nociceptor-like neurons.
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SATELLITE cells ,NEUROGLIA ,SENSORY receptors ,NEURONS ,PERIPHERAL nervous system - Abstract
A recent preprint abstract from biorxiv.org discusses the potential use of satellite glial cells (SGCs) as a source for regenerating peripheral sensory neurons. The study found that adult mouse dorsal root ganglia (DRG) contain SGC-like cells that can dedifferentiate into glial sensory progenitor cells in vitro. By coexpressing certain transcription factors, these cells were induced to develop into nociceptor-like neurons, which express marker ion channels associated with pain sensation. This research suggests that glial cells from the adult DRG have neural stem cell-like properties and could be valuable for future neural repair strategies in the peripheral nervous system. However, it is important to note that this preprint has not yet undergone peer review. [Extracted from the article]
- Published
- 2024
9. The Effects of Viral Infections on the Molecular and Signaling Pathways Involved in the Development of the PAOs.
- Author
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Liu, Xiaozhou, Zhao, Zhengdong, Shi, Xinyu, Zong, Yanjun, and Sun, Yu
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EAR diseases ,CONGENITAL disorders ,VIRUS diseases ,CYTOMEGALOVIRUS diseases ,CELLULAR signal transduction - Abstract
Cytomegalovirus infection contributes to 10–30% of congenital hearing loss in children. Vertebrate peripheral auditory organs include the outer, middle, and inner ear. Their development is regulated by multiple signaling pathways. However, most ear diseases due to viral infections are due to congenital infections and reactivation and affect healthy adults to a lesser extent. This may be due to the fact that viral infections affect signaling pathways that are important for the development of peripheral hearing organs. Therefore, an in-depth understanding of the relationship between viral infections and the signaling pathways involved in the development of peripheral hearing organs is important for the prevention and treatment of ear diseases. In this review, we summarize the effects of viruses on signaling pathways and signaling molecules in the development of peripheral auditory organs. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Modern In Vitro Techniques for Modeling Hearing Loss.
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Shah, Jamie J., Jimenez-Jaramillo, Couger A., Lybrand, Zane R., Yuan, Tony T., and Erbele, Isaac D.
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BIOPRINTING ,HAIR cells ,HEARING disorders ,INNER ear diseases ,SENSORINEURAL hearing loss ,MOLECULAR switches ,COCHLEA physiology - Abstract
Sensorineural hearing loss (SNHL) is a prevalent and growing global health concern, especially within operational medicine, with limited therapeutic options available. This review article explores the emerging field of in vitro otic organoids as a promising platform for modeling hearing loss and developing novel therapeutic strategies. SNHL primarily results from the irreversible loss or dysfunction of cochlear mechanosensory hair cells (HCs) and spiral ganglion neurons (SGNs), emphasizing the need for innovative solutions. Current interventions offer symptomatic relief but do not address the root causes. Otic organoids, three-dimensional multicellular constructs that mimic the inner ear's architecture, have shown immense potential in several critical areas. They enable the testing of gene therapies, drug discovery for sensory cell regeneration, and the study of inner ear development and pathology. Unlike traditional animal models, otic organoids closely replicate human inner ear pathophysiology, making them invaluable for translational research. This review discusses methodological advances in otic organoid generation, emphasizing the use of human pluripotent stem cells (hPSCs) to replicate inner ear development. Cellular and molecular characterization efforts have identified key markers and pathways essential for otic organoid development, shedding light on their potential in modeling inner ear disorders. Technological innovations, such as 3D bioprinting and microfluidics, have further enhanced the fidelity of these models. Despite challenges and limitations, including the need for standardized protocols and ethical considerations, otic organoids offer a transformative approach to understanding and treating auditory dysfunctions. As this field matures, it holds the potential to revolutionize the treatment landscape for hearing and balance disorders, moving us closer to personalized medicine for inner ear conditions. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Unraveling the Mechanisms of Vestibular Neuron Formation from Human Induced Pluripotent Stem Cells.
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Norton, Benjamin, Quirk, Analia, and Matsuoka, Akihiro J.
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- 2024
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12. Increased Type I and Decreased Type II Hair Cells after Deletion of Sox2 in the Developing Mouse Utricle.
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Lu, Jingrong, Hu, Lingxiang, Ye, Bin, Hu, Haixia, Tao, Yong, Shu, Yilai, Hao Chiang, Borse, Vikrant, Xiang, Mingliang, Wu, Hao, Edge, Albert S.B., and Shi, Fuxin
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HAIR cells , *CELL determination , *FATE mapping (Genetics) , *PROGENITOR cells , *TRANSGENIC mice - Abstract
• Sox2 knockout in HCs increased the number of Type I HCs and decreased the number of Type II HCs. • The effect of Sox2 -knockout persisted into adulthood, resulting in an increased number of Type I HCs. • The results demonstrated that SOX2 plays a critical role in Type I and Type II HC fate determination. The vestibular system of the inner ear contains Type I and Type II hair cells (HCs) generated from sensory progenitor cells; however, little is known about how the HC subtypes are formed. Sox2 (encoding SRY-box 2) is expressed in Type II, but not in Type I, HCs. The present study aimed to investigate the role of SOX2 in cell fate determination in Type I vs. Type II HCs. First, we confirmed that Type I HCs developed from Sox2- expressing cells through lineage tracing of Sox2- positive cells using a CAG-tdTomato reporter mouse crossed with a Sox2-CreER mouse. Then, Sox2 loss of function was induced in HCs, using Sox2 flox transgenic mice crossed with a Gfi1-Cre driver mouse. Knockout of Sox2 in HCs increased the number of Type I HCs and decreased the number of Type II HCs, while the total number of HCs and Sox2- positive supporting cells did not change. In addition, the effect of Sox2 -knockout persisted into adulthood, resulting in an increased number of Type I HCs. These results demonstrate that SOX2 plays a critical role in the determination of Type II vs. Type I HC fate. The results suggested that Sox2 is a potential target for generating Type I HCs, which may be important for regenerative strategies for balance disorders. [ABSTRACT FROM AUTHOR]
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- 2019
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13. Strategies for Stem Cell-Based Therapy for Inner Ear Cochlear Regeneration.
- Author
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Peyvandi, Ali Asghar, Abbaszadeh, Hojjat-Allah, Khoshsirat, Shahrokh, Zali, Alireza, and Niknazar, Somayeh
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INNER ear ,CORTI'S organ ,AUDITORY neurons ,HAIR cells ,NERVOUS system regeneration ,SENSORINEURAL hearing loss - Abstract
The organ of Corti of mammals has an organized structure in which row of inner and outer hair cells (HCs) are enclosed within the numerous cells on the basilar membrane. Given the prevalence of sensorineural hearing loss due to aging and acoustic insult, it is highly desirable to develop a protocol that produces cochlear sensory cells and their associated spiral sensory neurons as a tool to advance understanding of inner ear development. The replacement of damaged auditory neurons holds promise for significantly improving clinical outcomes in deaf patients. Cell therapy is one of the treatment options for deafness. The progress in cell therapy and reprogramming techniques has opened avenues to stimulate either endogenous or transplanted stem cells, aiming to replace and repair damaged inner ear HCs and restore auditory function. In fact, current research focuses on generating functional HCs. Various approaches are being explored to regenerate auditory HCs and facilitate neural connections. Here is an overview of existing experimental culture setups for the HCs and auditory neurons regeneration and their potential treatment for hearing disorders [ABSTRACT FROM AUTHOR]
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- 2023
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14. Recent Therapeutic Progress and Future Perspectives for the Treatment of Hearing Loss.
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Lye, Joey, Delaney, Derek S., Leith, Fiona K., Sardesai, Varda S., McLenachan, Samuel, Chen, Fred K., Atlas, Marcus D., and Wong, Elaine Y. M.
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PRESBYCUSIS ,HEARING disorders ,HAIR cells ,SENSORINEURAL hearing loss ,SPIRAL ganglion ,INNER ear - Abstract
Up to 1.5 billion people worldwide suffer from various forms of hearing loss, with an additional 1.1 billion people at risk from various insults such as increased consumption of recreational noise-emitting devices and ageing. The most common type of hearing impairment is sensorineural hearing loss caused by the degeneration or malfunction of cochlear hair cells or spiral ganglion nerves in the inner ear. There is currently no cure for hearing loss. However, emerging frontier technologies such as gene, drug or cell-based therapies offer hope for an effective cure. In this review, we discuss the current therapeutic progress for the treatment of hearing loss. We describe and evaluate the major therapeutic approaches being applied to hearing loss and summarize the key trials and studies. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Mapping oto-pharyngeal development in a human inner ear organoid model.
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Steinhart, Matthew R., van der Valk, Wouter H., Osorio, Daniel, Serdy, Sara A., Jingyuan Zhang, Nist-Lund, Carl, Jin Kim, Moncada-Reid, Cynthia, Liang Sun, Jiyoon Lee, and Koehler, Karl R.
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INNER ear ,HUMAN biology ,STEM cell culture ,PLURIPOTENT stem cells ,TISSUE differentiation ,HAIR cells - Abstract
Inner ear development requires the coordination of cell types from distinct epithelial, mesenchymal and neuronal lineages. Although we have learned much from animal models, many details about human inner ear development remain elusive. We recently developed an in vitro model of human inner ear organogenesis using pluripotent stem cells in a 3D culture, fostering the growth of a sensorineural circuit, including hair cells and neurons. Despite previously characterizing some cell types, many remain undefined. This study aimed to chart the in vitro development timeline of the inner ear organoid to understand the mechanisms at play. Using singlecell RNA sequencing at ten stages during the first 36 days of differentiation, we tracked the evolution from pluripotency to various ear cell types after exposure to specific signaling modulators. Our findings showcase gene expression that influences differentiation, identifying a plethora of ectodermal and mesenchymal cell types. We also discern aspects of the organoid model consistent with in vivo development, while highlighting potential discrepancies. Our study establishes the Inner Ear Organoid Developmental Atlas (IODA), offering deeper insights into human biology and improving inner ear tissue differentiation. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Neuromast hair cells retain the capacity of regeneration during heavy metal exposure.
- Author
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Montalbano, G., Laurà, R., Abbate, F., Levanti, M., Guerrera, M.C., Ciriaco, E., Germanà, A., and Capillo, G.
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HAIR cells ,REGENERATION (Biology) ,HEAVY metals in the body ,ZEBRA danio ,IMMUNOHISTOCHEMISTRY ,LATERAL line organs - Abstract
The neuromast is the morphological unit of the lateral line of fishes and is composed of a cluster of central sensory cells (hair cells) surrounded by support and mantle cells. Heavy metals exposure leads to disruption of hair cells within the neuromast. It is well known that the zebrafish has the ability to regenerate the hair cells after damage caused by toxicants. The process of regeneration depends on proliferation, differentiation and cellular migration of sensory and non-sensory progenitor cells. Therefore, our study was made in order to identify which cellular types are involved in the complex process of regeneration during heavy metals exposure. For this purpose, adult zebrafish were exposed to various heavy metals (Arsenic, cadmium and zinc) for 72 h. After acute (24 h) exposure, immunohistochemical localization of S100 (a specific marker for hair cells) in the neuromasts highlighted the hair cells loss. The immunoreaction for Sox2 (a specific marker for stem cells), at the same time, was observed in the support and mantle cells, after exposure to arsenic and cadmium, while only in the support cells after exposure to zinc. After chronic (72 h) exposure the hair cells were regenerated, showing an immunoreaction for S100 protein. At the same exposure time to the three metals, a Sox2 immunoreaction was expressed in support and mantle cells. Our results showed for the first time the regenerative capacity of hair cells, not only after, but also during exposure to heavy metals, demonstrated by the presence of different stem cells that can diversify in hair cells. [ABSTRACT FROM AUTHOR]
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- 2018
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17. The role of epigenetic modifications in sensory hair cell development, survival, and regulation.
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Ying Xiao and Dan Li
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HAIR cells ,SENSE organs ,SENSORINEURAL hearing loss ,EPIGENETICS ,INNER ear - Abstract
The cochlea is the sensory organ in the periphery, and hair cells are its main sensory cells. The development and survival of hair cells are highly controlled processes. When cells face intracellular and environmental stimuli, epigenetic regulation controls the structure and function of the genome in response to different cell fates. During sensory hair cell development, different histone modifications can induce normal numbers of functional hair cells to generate. When individuals are exposed to environmental-related hair cell damage, epigenetic modification also plays a significant role in the regulation of hair cell fate. Since mammalian hair cells cannot regenerate, their loss can cause permanent sensorineural hearing loss. Many breakthroughs have been achieved in recent years in understanding the signaling pathways that determine hair cell regeneration, and it is fascinating to note that epigenetic regulation plays a significant role in hair cell regeneration. In this review, we discuss the role of epigenetics in inner ear cell development, survival and regeneration and the significant impact on hearing protection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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18. The ndrg2 Gene Regulates Hair Cell Morphogenesis and Auditory Function during Zebrafish Development.
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Wang, Cheng, Wang, Xin, Zheng, Hao, Yao, Jia, Xiang, Yuqing, and Liu, Dong
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HAIR cells ,NOTCH signaling pathway ,NUCLEIC acid hybridization ,BRACHYDANIO ,SENSORINEURAL hearing loss ,MORPHOGENESIS ,TUMOR suppressor genes - Abstract
Damages of sensory hair cells (HCs) are mainly responsible for sensorineural hearing loss, however, its pathological mechanism is not yet fully understood due to the fact that many potential deafness genes remain unidentified. N-myc downstream-regulated gene 2 (ndrg2) is commonly regarded as a tumor suppressor and a cell stress-responsive gene extensively involved in cell proliferation, differentiation, apoptosis and invasion, while its roles in zebrafish HC morphogenesis and hearing remains unclear. Results of this study suggested that ndrg2 was highly expressed in the HCs of the otic vesicle and neuromasts via in situ hybridization and single-cell RNA sequencing. Ndrg2 loss-of-function larvae showed decreased crista HCs, shortened cilia, and reduced neuromasts and functional HCs, which could be rescued by the microinjection of ndrg2 mRNA. Moreover, ndrg2 deficiency induced attenuated startle response behaviors to sound vibration stimuli. Mechanistically, there were no detectable HC apoptosis and supporting cell changes in the ndrg2 mutants, and HCs were capable of recovering by blocking the Notch signaling pathway, suggesting that ndrg2 was implicated in HC differentiation mediated by Notch. Overall, our study demonstrates that ndrg2 plays crucial roles in HC development and auditory sensory function utilizing the zebrafish model, which provides new insights into the identification of potential deafness genes and regulation mechanism of HC development. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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19. Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions.
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Smith-Cortinez, Natalia, Tan, A. Katherine, Stokroos, Robert J., Versnel, Huib, and Straatman, Louise V.
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HAIR cells ,REGENERATION (Biology) ,NOTCH genes ,COCHLEA ,INNER ear ,COCHLEA physiology ,SPIRAL ganglion ,PROGENITOR cells - Abstract
Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFβ signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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20. Application of Human Stem Cells to Model Genetic Sensorineural Hearing Loss and Meniere Disease.
- Author
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Lamolda, Mar, Frejo, Lidia, Gallego-Martinez, Alvaro, and Lopez-Escamez, Jose A.
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SENSORINEURAL hearing loss ,MENIERE'S disease ,HUMAN stem cells ,INNER ear ,GENETIC models ,PLURIPOTENT stem cells - Abstract
Genetic sensorineural hearing loss and Meniere disease have been associated with rare variations in the coding and non-coding region of the human genome. Most of these variants were classified as likely pathogenic or variants of unknown significance and require functional validation in cellular or animal models. Given the difficulties to obtain human samples and the raising concerns about animal experimentation, human-induced pluripotent stem cells emerged as cellular models to investigate the interaction of genetic and environmental factors in the pathogenesis of inner ear disorders. The generation of human sensory epithelia and neuron-like cells carrying the variants of interest may facilitate a better understanding of their role during differentiation. These cellular models will allow us to explore new strategies for restoring hearing and vestibular sensory epithelia as well as neurons. This review summarized the use of human-induced pluripotent stem cells in sensorineural hearing loss and Meniere disease and proposed some strategies for its application in clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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21. Early Wnt Signaling Activation Promotes Inner Ear Differentiation via Cell Caudalization in Mouse Stem Cell-Derived Organoids.
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Tang, Pei-Ciao, Chen, Li, Singh, Sunita, Groves, Andrew K, Koehler, Karl R, Liu, Xue Zhong, and Nelson, Rick F
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INNER ear ,CELL differentiation ,WNT signal transduction ,ORGANOIDS ,RNA sequencing ,CELLULAR signal transduction - Abstract
The inner ear is derived from the otic placode, one of the numerous cranial sensory placodes that emerges from the pre-placodal ectoderm (PPE) along its anterior-posterior axis. However, the molecular dynamics underlying how the PPE is regionalized are poorly resolved. We used stem cell-derived organoids to investigate the effects of Wnt signaling on early PPE differentiation and found that modulating Wnt signaling significantly increased inner ear organoid induction efficiency and reproducibility. Alongside single-cell RNA sequencing, our data reveal that the canonical Wnt signaling pathway leads to PPE regionalization and, more specifically, medium Wnt levels during the early stage induce (1) expansion of the caudal neural plate border (NPB), which serves as a precursor for the posterior PPE, and (2) a caudal microenvironment that is required for otic specification. Our data further demonstrate Wnt-mediated induction of rostral and caudal cells in organoids and more broadly suggest that Wnt signaling is critical for anterior-posterior patterning in the PPE. Graphical Abstract [ABSTRACT FROM AUTHOR]
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- 2023
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22. مروری بر کاربرد سلولهای بنیادی در طب نظامي.
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مصطفي اکبریقمي, طاهر علمي, محسن چمنآرا, and رضا حیدری
- Subjects
STEM cell transplantation ,INJURY complications ,WOUND care ,SKELETAL muscle ,MILITARY medicine ,WAR ,SKIN ,ANTI-inflammatory agents ,GROWTH factors ,GUIDED tissue regeneration ,UMBILICAL cord ,AMNIOTIC liquid ,CELL physiology ,PLACENTA ,CELL proliferation ,HEMATOPOIETIC stem cell transplantation ,BONE marrow ,ADIPOSE tissues ,MESENCHYMAL stem cells - Abstract
War's nature is constantly changing over time with the progress in military technology and weapons of war, which has led to a diverse pattern of tissue injuries. Developments in personal protective equipment and body armor, rapid transfer from the battlefield to medical centers, improved resuscitation measures, bleeding control, and wound management have increasingly contributed to the wounded survival. However, the injured suffer tissue injuries of various degrees, thereby undergoing complicated and prolonged treatments. An increasing incidence of injuries caused by explosive devices in modern wars has more complicated treatment and recovery of the injured, highlighting the need for modern treatment methods based on stem cells in military medicine. Stem cells can be harvested from various sources such as bone marrow, adipose tissue, skeletal muscle, skin, umbilical cord blood and Wharton's jelly, placenta and amniotic fluid, and with the ability of self-renewal, proliferation, and differentiation into functional cells of different tissues, anti-inflammatory, paracrine and immune system modulating activities have been considered as a promising therapeutic approach to many battlefield injuries and their complications. Recent research in this area reveals the development of solutions to reduce critical consequences when facing the injuries caused by warfare. Thereby, in this review, in addition to outlining the most important tissue injuries in modern combat, recent developments in the use of stem cells for the regeneration of injured tissues have been highlighted. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. Sufu- and Spop-mediated regulation of Gli2 is essential for the control of mammalian cochlear hair cell differentiation.
- Author
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Tianli Qin, Chin Chung Ho, Boshi Wang, Chi-Chung Hui, and Mai Har Sham
- Subjects
HAIR cells ,CELL differentiation ,CORTI'S organ ,GENE expression ,CELL cycle - Abstract
Development of mammalian auditory epithelium, the organ of Corti, requires precise control of both cell cycle withdrawal and differentiation. Sensory progenitors (prosensory cells) in the cochlear apex exit the cell cycle first but differentiate last. Sonic hedgehog (Shh) signaling is required for the spatiotemporal regulation of prosensory cell differentiation, but the underlying mechanisms remain unclear. Here, we show that suppressor of fused (Sufu), a negative regulator of Shh signaling, is essential for controlling the timing and progression of hair cell (HC) differentiation. Removal of Sufu leads to abnormal Atoh1 expression and a severe delay of HC differentiation due to elevated Gli2 mRNA expression. Later in development, HC differentiation defects are restored in the Sufu mutant by the action of speckle-type PDZ protein (Spop), which promotes Gli2 protein degradation. Deletion of both Sufu and Spop results in robust Gli2 activation, exacerbating HC differentiation defects. We further demonstrate that Gli2 inhibits HC differentiation through maintaining the progenitor state of Sox2+ prosensory cells. Along the basal-apical axis of the developing cochlea, the Sox2 expression level is higher in the progenitor cells than in differentiating cells and is down-regulated from base to apex as differentiation proceeds. The dynamic spatiotemporal change of Sox2 expression levels is controlled by Shh signaling through Gli2. Together, our results reveal key functions of Gli2 in sustaining the progenitor state, thereby preventing HC differentiation and in turn governing the basal-apical progression of HC differentiation in the cochlea. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
24. Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss.
- Author
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Durán-Alonso, María Beatriz and Petković, Hrvoje
- Subjects
PLURIPOTENT stem cells ,INDUCED pluripotent stem cells ,HEARING disorders ,INNER ear ,COCHLEAR implants - Abstract
Hearing loss is the most prevalent sensorineural impairment in humans. Yet despite very active research, no effective therapy other than the cochlear implant has reached the clinic. Main reasons for this failure are the multifactorial nature of the disorder, its heterogeneity, and a late onset that hinders the identification of etiological factors. Another problem is the lack of human samples such that practically all the work has been conducted on animals. Although highly valuable data have been obtained from such models, there is the risk that inter-species differences exist that may compromise the relevance of the gathered data. Human-based models are therefore direly needed. The irruption of human induced pluripotent stem cell technologies in the field of hearing research offers the possibility to generate an array of otic cell models of human origin; these may enable the identification of guiding signalling cues during inner ear development and of the mechanisms that lead from genetic alterations to pathology. These models will also be extremely valuable when conducting ototoxicity analyses and when exploring new avenues towards regeneration in the inner ear. This review summarises some of the work that has already been conducted with these cells and contemplates future possibilities. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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25. Genetic Mechanism Study of Auditory Phoenix Spheres and Transcription Factors Prediction for Direct Reprogramming by Bioinformatics.
- Author
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Chen, Jishizhan, Liu, Ziyu, and Chang, Jinke
- Subjects
INDUCED pluripotent stem cells ,TRANSCRIPTION factors ,HAIR cells - Abstract
Background: Hearing loss is the most common irreversible sensory disorder. By delivering regenerative cells into the cochlea, cell-based therapy provides a novel strategy for hearing restoration. Recently, newly-identified phoenix cells have drawn attention due to their nearly unlimited self-renewal and neural differentiation capabilities. They are a promising cell source for cell therapy and a potential substitute for induced pluripotent stem cells (iPSCs) in many in vitro applications. However, the underlying genomic mechanism of their self-renewal capabilities is largely unknown. The aim of this study was to identify hub genes and potential molecular mechanisms between differentiated and undifferentiated phoenix cells and predict transcription factors (TFs) for direct reprogramming. Material and Methods: The datasets were downloaded from the ArrayExpress database. Samples of differentiated and undifferentiated phoenix cells with three biological replicates were utilised for bioinformatic analysis. Differentially expressed genes (DEGs) were screened and the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were investigated. The gene set enrichment analysis (GSEA) was conducted to verify the enrichment of four self-defined gene set collections, followed by protein-protein interaction (PPI) network construction and subcluster analysis. The prediction of TFs for direct reprogramming was performed based on the TRANSFAC database. Results: Ten hub genes were identified to be the key candidates for self-renewal. Ten TFs were predicted as the direct reprogramming factors. This study provides a theoretical foundation for understanding phoenix cells and clues for direct reprogramming, which would stimulate further experiments and clinical applications in hearing research and treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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26. Elevated exposures to persistent endocrine disrupting compounds impact the sperm methylome in regions associated with autism spectrum disorder.
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Maggio, Angela G., Shu, Henry T., Laufer, Benjamin I., Chongfeng Bi, Yinglei Lai, LaSalle, Janine M., and Hu, Valerie W.
- Subjects
ENDOCRINE disruptors ,AUTISM spectrum disorders ,PERSISTENT pollutants ,SPERMATOZOA ,HUMAN gene mapping ,FRUIT ripening - Abstract
Environmental exposures to endocrine disrupting compounds (EDCs) such as the organochlorines have been linked with various diseases including neurodevelopmental disorders. Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder that is considered strongly genetic in origin due to its high heritability. However, the rapidly rising prevalence of ASD suggests that environmental factors may also influence risk for ASD. In the present study, whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of men from the Faroe Islands (Denmark) who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a primary breakdown product of the now banned insecticide dichlorodiphenyltrichloroethane (DDT). Aside from being considered a genetic isolate, inhabitants of the Faroe Islands have a native diet that potentially exposes them to a wide range of seafood neurotoxicants in the form of persistent organic pollutants (POPs). The DMRs were mapped to the human genome using Bismark, a 3-letter aligner used for methyl-seq analyses. Gene ontology, functional, and pathway analyses of the DMR-associated genes showed significant enrichment for genes involved in neurological functions and neurodevelopmental processes frequently impacted by ASD. Notably, these genes also significantly overlap with autism risk genes as well as those previously identified in sperm from fathers of children with ASD in comparison to that of fathers of neurotypical children. These results collectively suggest a possible mechanism involving altered methylation of a significant number of neurologically relevant ASD risk genes for introducing epigenetic changes associated with environmental exposures into the sperm methylome. Such changes may provide the potential for transgenerational inheritance of ASD as well as other disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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27. WNT Activation and TGFβ-Smad Inhibition Potentiate Stemness of Mammalian Auditory Neuroprogenitors for High-Throughput Generation of Functional Auditory Neurons In Vitro.
- Author
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Rousset, Francis, Schilardi, Giulia, Sgroi, Stéphanie, Nacher-Soler, German, Sipione, Rebecca, Kleinlogel, Sonja, and Senn, Pascal
- Subjects
AUDITORY neurons ,HAIR cells ,INNER ear ,SENSORINEURAL hearing loss ,PROGENITOR cells ,HIGH throughput screening (Drug development) - Abstract
Hearing loss affects over 460 million people worldwide and is a major socioeconomic burden. Both genetic and environmental factors (i.e., noise overexposure, ototoxic drug treatment and ageing), promote the irreversible degeneration of cochlear hair cells and associated auditory neurons, leading to sensorineural hearing loss. In contrast to birds, fish and amphibians, the mammalian inner ear is virtually unable to regenerate due to the limited stemness of auditory progenitors, and no causal treatment is able to prevent or reverse hearing loss. As of today, a main limitation for the development of otoprotective or otoregenerative therapies is the lack of efficient preclinical models compatible with high-throughput screening of drug candidates. Currently, the research field mainly relies on primary organotypic inner ear cultures, resulting in high variability, low throughput, high associated costs and ethical concerns. We previously identified and characterized the phoenix auditory neuroprogenitors (ANPGs) as highly proliferative progenitor cells isolated from the A/J mouse cochlea. In the present study, we aim at identifying the signaling pathways responsible for the intrinsic high stemness of phoenix ANPGs. A transcriptomic comparison of traditionally low-stemness ANPGs, isolated from C57Bl/6 and A/J mice at early passages, and high-stemness phoenix ANPGs was performed, allowing the identification of several differentially expressed pathways. Based on differentially regulated pathways, we developed a reprogramming protocol to induce high stemness in presenescent ANPGs (i.e., from C57Bl6 mouse). The pharmacological combination of the WNT agonist (CHIR99021) and TGFβ/Smad inhibitors (LDN193189 and SB431542) resulted in a dramatic increase in presenescent neurosphere growth, and the possibility to expand ANPGs is virtually limitless. As with the phoenix ANPGs, stemness-induced ANPGs could be frozen and thawed, enabling distribution to other laboratories. Importantly, even after 20 passages, stemness-induced ANPGs retained their ability to differentiate into electrophysiologically mature type I auditory neurons. Both stemness-induced and phoenix ANPGs resolve a main bottleneck in the field, allowing efficient, high-throughput, low-cost and 3R-compatible in vitro screening of otoprotective and otoregenerative drug candidates. This study may also add new perspectives to the field of inner ear regeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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28. Reversible and bidirectional signaling of notch ligands.
- Author
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Vázquez-Ulloa, Elenaé, Lin, Kai-Lan, Lizano, Marcela, and Sahlgren, Cecilia
- Subjects
NOTCH signaling pathway ,LIGANDS (Biochemistry) ,NOTCH genes ,CELL receptors ,TELECOMMUNICATION systems - Abstract
The Notch signaling pathway is a direct cell-cell communication system involved in a wide variety of biological processes, and its disruption is observed in several pathologies. The pathway is comprised of a ligand-expressing (sender) cell and a receptor-expressing (receiver) cell. The canonical ligands are members of the Delta/Serrate/Lag-1 (DSL) family of proteins. Their binding to a Notch receptor in a neighboring cell induces a conformational change in the receptor, which will undergo regulated intramembrane proteolysis (RIP), liberating the Notch intracellular domain (NICD). The NICD is translocated to the nucleus and promotes gene transcription. It has been demonstrated that the ligands can also undergo RIP and nuclear translocation, suggesting a function for the ligands in the sender cell and possible bidirectionality of the Notch pathway. Although the complete mechanism of ligand processing is not entirely understood, and its dependence on Notch receptors has not been ruled out. Also, ligands have autonomous functions beyond Notch activation. Here we review the concepts of reverse and bidirectional signalization of DSL proteins and discuss the characteristics that make them more than just ligands of the Notch pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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29. Identification of stage-specific markers during differentiation of hair cells from mouse inner ear stem cells or progenitor cells in vitro.
- Author
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Liu, Quanwen, Chen, Jiarong, Gao, Xiangli, Ding, Jie, Tang, Zihua, Zhang, Cui, Chen, Jianling, Li, Liang, Chen, Ping, and Wang, Jinfu
- Subjects
- *
BIOMARKERS , *CELL differentiation , *HAIR cells , *STEM cells , *PROGENITOR cells , *INNER ear , *LABORATORY mice - Abstract
The induction of inner ear hair cells from stem cells or progenitor cells in the inner ear proceeds through a committed inner ear sensory progenitor cell stage prior to hair cell differentiation. To increase the efficacy of inducing inner ear hair cell differentiation from the stem cells or progenitor cells, it is essential to identify comprehensive markers for the stem cells/progenitor cells from the inner ear, the committed inner ear sensory progenitor cells and the differentiating hair cells to optimize induction conditions. Here, we report that we efficiently isolated and expanded the stem cells or progenitor cells from postnatal mouse cochleae, and induced the generation of inner ear progenitor cells and subsequent differentiation of hair cells. We profiled the gene expression of the stem cells or progenitor cells, the inner ear progenitor cells, and hair cells using aRNA microarray analysis. The pathway and gene ontology (GO) analysis of differentially expressed genes was performed. Analysis of genes exclusively detected in one particular cellular population revealed 30, 38, and 31 genes specific for inner ear stem cells, inner ear progenitor cells, and hair cells, respectively. We further examined the expression of these genes in vivo and determined that Gdf10+Ccdc121, Tmprss9+Orm1, and Chrna9+Espnl are marker genes specific for inner ear stem cells, inner ear progenitor cells, and differentiating hair cells, respectively. The identification of these marker genes will likely help the effort to increase the efficacy of hair cell induction from the stem cells or progenitor cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
30. Understanding the Notch Signaling Pathway in Acute Myeloid Leukemia Stem Cells: From Hematopoiesis to Neoplasia.
- Author
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Láinez-González, Daniel, Serrano-López, Juana, and Alonso-Dominguez, Juan Manuel
- Subjects
CARCINOGENESIS ,ACUTE myeloid leukemia ,CELL receptors ,METABOLISM ,CELLULAR signal transduction ,STEM cells ,HEMATOPOIESIS - Abstract
Simple Summary: We review the state of the art of knowledge regarding the Notch signaling pathway to shed light on the role that this pathway has in hematopoiesis and hematological neoplasia, focusing on acute myeloid leukemia. The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs seem to be the principal cause of patient relapse. This population is in a quiescent state. Signaling pathways that govern this process must be understood to increase the chemosensitivity of this compartment. In this review, we focus on the conserved Notch signaling pathway, and its repercussions in hematopoiesis and hematological neoplasia. We found in the literature both visions regarding Notch activity in acute myeloid leukemia. On one hand, the activation of Notch leads to cell proliferation, on the other hand, the activation of Notch leads to cell cycle arrest. This dilemma requires further experiments to be answered, in order to understand the role of Notch not only in acute myeloid leukemia, but especially in LSCs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
31. Age-Related Hearing Loss: Sensory and Neural Etiology and Their Interdependence.
- Author
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Elliott, Karen L., Fritzsch, Bernd, Yamoah, Ebenezer N., and Zine, Azel
- Subjects
HAIR cells ,INFERIOR colliculus ,HEARING disorders ,COCHLEAR nucleus ,SPIRAL ganglion ,COCHLEAR implants ,OLDER people ,AUDITORY evoked response ,NEURONS ,COCHLEA ,AGE distribution ,AUDITORY perception ,TRANSCRIPTION factors ,BRAIN stem - Abstract
Age-related hearing loss (ARHL) is a common, increasing problem for older adults, affecting about 1 billion people by 2050. We aim to correlate the different reductions of hearing from cochlear hair cells (HCs), spiral ganglion neurons (SGNs), cochlear nuclei (CN), and superior olivary complex (SOC) with the analysis of various reasons for each one on the sensory deficit profiles. Outer HCs show a progressive loss in a basal-to-apical gradient, and inner HCs show a loss in a apex-to-base progression that results in ARHL at high frequencies after 70 years of age. In early neonates, SGNs innervation of cochlear HCs is maintained. Loss of SGNs results in a considerable decrease (~50% or more) of cochlear nuclei in neonates, though the loss is milder in older mice and humans. The dorsal cochlear nuclei (fusiform neurons) project directly to the inferior colliculi while most anterior cochlear nuclei reach the SOC. Reducing the number of neurons in the medial nucleus of the trapezoid body (MNTB) affects the interactions with the lateral superior olive to fine-tune ipsi- and contralateral projections that may remain normal in mice, possibly humans. The inferior colliculi receive direct cochlear fibers and second-order fibers from the superior olivary complex. Loss of the second-order fibers leads to hearing loss in mice and humans. Although ARHL may arise from many complex causes, HC degeneration remains the more significant problem of hearing restoration that would replace the cochlear implant. The review presents recent findings of older humans and mice with hearing loss. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
32. Induction of the inner ear: Stepwise specification of otic fate from multipotent progenitors
- Author
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Chen, Jingchen and Streit, Andrea
- Subjects
- *
INNER ear , *PROGENITOR cells , *EPITHELIUM , *TRANSCRIPTION factors , *CELLULAR signal transduction , *STEM cells , *GENE regulatory networks - Abstract
Abstract: Despite its complexity in the adult, during development the inner ear arises from a simple epithelium, the otic placode. Placode specification is a multistep process that involves the integration of various signalling pathways and downstream transcription factors in time and space. Here we review the molecular events that successively commit multipotent ectodermal precursors to the otic lineage. The first step in this hierarchy is the specification of sensory progenitor cells, which can contribute to all sensory placodes, followed by the induction of a common otic–epibranchial field and finally the establishment the otic territory. In recent years, some of the molecular components that control this process have been identified, and begin to reveal complex interactions. Future studies will need to unravel how this information is integrated and encoded in the genome. This will form the blueprint for stem cell differentiation towards otic fates and generate a predictive gene regulatory network that models the earliest steps of otic specification. [Copyright &y& Elsevier]
- Published
- 2013
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33. Towards maturation of human otic hair cell–like cells in pluripotent stem cell–derived organoid transplants.
- Author
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Moeinvaziri, Farideh, Shojaei, Amir, Haghparast, Newsha, Yakhkeshi, Saeed, Nemati, Shadman, Hassani, Seyedeh-Nafiseh, and Baharvand, Hossein
- Subjects
HAIR cells ,PLURIPOTENT stem cells ,INNER ear ,HAIR ,MESENCHYMAL stem cells ,CHORIOALLANTOIS ,CHICKEN embryos - Abstract
Human otic organoids generated from pluripotent stem cells (PSCs) provide a promising platform for modeling, drug testing, and cell-based therapies of inner ear diseases. However, providing the appropriate niche that resembles inner ear development and its vasculature to generate otic organoids is less conspicuous. Here, we devised a strategy to enhance maturation of otic progenitor cells toward human hair cell–like cells (HCLCs) by assembling three-dimensional (3D) otic organoids that contain human PSC-derived otic cells, endothelial cells, and mesenchymal stem cells (MSCs). Heterotopic implantation of otic organoids, designated as grafted otic organoids (GOs), in ex ovo chick embryo chorioallantoic membrane (CAM) stimulated maturation of the HCLCs. Functional analysis revealed the presence of voltage-gated potassium currents without detectable sodium currents in these cells in the GOs. Our results demonstrated that implantation of 3D heterotypic cell mixtures of otic organoids improved maturation of human HCLCs. This GO-derived HCLCs could be an attractive source for drug discovery and other biomedical applications. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
34. Towards a gene regulatory network for otic and epibranchial specification
- Author
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Tambalo, Monica, Streit, Andrea, and Basson, Michiel Albertus
- Subjects
571.8 - Abstract
Vertebrate sensory organs arise from the pre-placodal region (PPR) at the border of the neural plate, specified early during development. Differential activation of signalling pathways along the rostro-caudal axis patterns this territory to give rise to distinct placodes and ultimately to the olfactory epithelium, lens, inner ear and cranial ganglia. The aim of this project is to further investigate how sensory progenitor cells are restricted in fate to become specified as otic and epibranchial cells. The otic placode is induced next to the developing hindbrain by a combination of FGF and WNT signalling, while the epibranchial placode is specified by sustained FGF signalling and BMPs. Downstream of these signals different transcription factors are activated sequentially to confer otic-epibranchial fate. However, their epistatic relationships and regulatory interactions are poorly understood. Gene regulatory networks (GRNs) are powerful tools to explain why cells behave the way they do and here I aim to uncover the network that controls otic-epibranchial specification. To this end, I have combined published data with results from new molecular screens to generate a preliminary GRN that contains around 50 otic and epibranchial specific transcription factors and their signalling inputs. To establish the hierarchical interaction between all network components and their response to otic inducing signals I designed systematic perturbation experiments and exploited NanoString technology to quantify each component in the same tissue sample. Manipulation of signalling inputs reveals a temporal hierarchy of otic specification genes and points to a highly dynamic interaction between them. To identify new epistatic relationships among otic transcription factors, I employed loss-of-function approaches for key network components. In a complementary approach, I investigated the contribution of FGF on the otic chromatin landscape by ChIP-seq for histone modifications. Bioinformatic tools were used to interpret the data and regulatory elements for early FGF response genes were identified experimentally. The emerging GRN will not only identify new key regulators for inner ear specification, but also the regulatory regions that integrate information to build a functional ear.
- Published
- 2015
35. pRb phosphorylation regulates the proliferation of supporting cells in gentamicin-damaged neonatal avian utricle
- Author
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Wu, Jingfang, Sun, Shan, Li, Wenyan, Chen, Yan, and Li, Huawei
- Abstract
The ability of nonmammalian vertebrates to regenerate hair cells (HCs) after damage-induced HC loss has stimulated and inspired research in the field of HC regeneration. The protein pRb encoded by retinoblastoma gene Rb1forces sensory progenitor cells to exit cell cycle and maintain differentiated HCs and supporting cells (SCs) in a quiescent state. pRb function is regulated by phosphorylation through the MEKERK or the pRbRaf-1 signaling pathway. In our previous study, we have shown that pRb phosphorylation is crucial for progenitor cell proliferation and survival during the early embryonic stage of avian otocyst sensory epithelium development. However, in damaged avian utricle, the role of pRb in regulating the cell cycling of SCs or HCs regeneration still remains unclear. To further elucidate the function of pRb phosphorylation on SCs re-entering the cell cycle triggered by gentamycin-induced HCs damage, we isolated neonatal chicken utricles and treated them with the MEK inhibitor U0126 or the pRbRaf-1 inhibitor RRD-251, respectively in vitro. We found that after gentamycin-induced HCs damage, pRb phosphorylation is important for the quiescent SCs re-entering the cell cycle in the neonatal chicken utricle. In addition, the proliferation of SCs decreased in a dose-dependent manner in response to both U0126 and RRD-251, which indicates that both the MEKERK and the pRbRaf-1 signaling pathway play important roles in pRb phosphorylation in damaged neonatal chicken utricle. Together, these findings on the function of pRb in damaged neonatal chicken utricle improve our understanding of the regulation of the cell cycle of SCs after HCs loss and may shed light on the mammalian HC regeneration from SCs in damaged organs.
- Published
- 2014
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- View/download PDF
36. Expression and Physiology of Voltage-Gated Sodium Channels in Developing Human Inner Ear.
- Author
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Quinn, Rikki K., Drury, Hannah R., Cresswell, Ethan T., Tadros, Melissa A., Nayagam, Bryony A., Callister, Robert J., Brichta, Alan M., and Lim, Rebecca
- Subjects
SODIUM channels ,INNER ear ,PHYSIOLOGY ,HAIR cells ,ION channels - Abstract
Sodium channel expression in inner ear afferents is essential for the transmission of vestibular and auditory information to the central nervous system. During development, however, there is also a transient expression of Na
+ channels in vestibular and auditory hair cells. Using qPCR analysis, we describe the expression of four Na+ channel genes, SCN5A (Nav1.5), SCN8A (Nav1.6), SCN9A (Nav1.7), and SCN10A (Nav1.8) in the human fetal cristae ampullares, utricle, and base, middle, and apex of the cochlea. Our data show distinct patterns of Na+ channel gene expression with age and between these inner ear organs. In the utricle, there was a general trend toward fold-change increases in expression of SCN8A, SCN9A, and SCN10A with age, while the crista exhibited fold-change increases in SCN5A and SCN8A and fold-change decreases in SCN9A and SCN10A. Fold-change differences of each gene in the cochlea were more complex and likely related to distinct patterns of expression based on tonotopy. Generally, the relative expression of SCN genes in the cochlea was greater than that in utricle and cristae ampullares. We also recorded Na+ currents from developing human vestibular hair cells aged 10–11 weeks gestation (WG), 12–13 WG, and 14+ WG and found there is a decrease in the number of vestibular hair cells that exhibit Na+ currents with increasing gestational age. Na+ current properties and responses to the application of tetrodotoxin (TTX; 1 μM) in human fetal vestibular hair cells are consistent with those recorded in other species during embryonic and postnatal development. Both TTX-sensitive and TTX-resistant currents are present in human fetal vestibular hair cells. These results provide a timeline of sodium channel gene expression in inner ear neuroepithelium and the physiological characterization of Na+ currents in human fetal vestibular neuroepithelium. Understanding the normal developmental timeline of ion channel gene expression and when cells express functional ion channels is essential information for regenerative technologies. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
37. A human induced pluripotent stem cell‐based modular platform to challenge sensorineural hearing loss.
- Author
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Zine, Azel, Messat, Yassine, and Fritzsch, Bernd
- Subjects
INDUCED pluripotent stem cells ,DEAFNESS ,HAIR cells ,DRUG use testing ,BIOLOGICAL assay - Abstract
The sense of hearing depends on a specialized sensory organ in the inner ear, called the cochlea, which contains the auditory hair cells (HCs). Noise trauma, infections, genetic factors, side effects of ototoxic drugs (ie, some antibiotics and chemotherapeutics), or simply aging lead to the loss of HCs and their associated primary neurons. This results in irreversible sensorineural hearing loss (SNHL) as in mammals, including humans; the inner ear lacks the capacity to regenerate HCs and spiral ganglion neurons. SNHL is a major global health problem affecting millions of people worldwide and provides a growing concern in the aging population. To date, treatment options are limited to hearing aids and cochlear implants. A major bottleneck for development of new therapies for SNHL is associated to the lack of human otic cell bioassays. Human induced pluripotent stem cells (hiPSCs) can be induced in two‐dimensional and three‐dimensional otic cells in vitro models that can generate inner ear progenitors and sensory HCs and could be a promising preclinical platform from which to work toward restoring SNHL. We review the potential applications of hiPSCs in the various biological approaches, including disease modeling, bioengineering, drug testing, and autologous stem cell based‐cell therapy, that offer opportunities to understand the pathogenic mechanisms of SNHL and identify novel therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
38. Human induced pluripotent stem cells and CRISPR/Cas‐mediated targeted genome editing: Platforms to tackle sensorineural hearing loss.
- Author
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Stojkovic, Miodrag, Han, Dongjun, Jeong, Minjin, Stojkovic, Petra, and Stankovic, Konstantina M.
- Subjects
DEAFNESS ,PLURIPOTENT stem cells ,GENOME editing ,CRISPRS ,INNER ear - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
39. Waardenburg syndrome type II in a Chinese pedigree caused by frameshift mutation in the SOX10 gene.
- Author
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Li Li, Jing Ma, Xiao-li He, Yuan-tao Zhou, Yu Zhang, Quan-dong Chen, Lin Zhang, Biao Ruan, and Tie-Song Zhang
- Subjects
FRAMESHIFT mutation ,CONGENITAL disorders ,GENETIC disorders ,PHENOTYPES ,SENSORINEURAL hearing loss - Abstract
Waardenburg syndrome (WS) is a congenital hereditary disease, attributed to the most common symptoms of sensorineural deafness and iris hypopigmentation. It is also known as the hearing-pigmentation deficient syndrome. Mutations on SOXl0 gene often lead to congenital deafness and has been shown to play an important role in the pathogenesis of WS. We investigated one family of five members, with four patients exhibiting the classic form of WS2, whose DNA samples were analyzed by the technique of Whole-exome sequencing (WES). From analysis of WES data, we found that both the mother and all three children in the family have a heterozygous mutation on the Sex Determining Region Y - Box 10 (SOX10) gene. The mutation was c.298 300delinsGG in exon 2 of SOX10 (NM 006941), which leads to a frameshift of nine nucleotides, hence the amino acids (p. S100Rfs*9) are altered and the protein translation may be terminated prematurely. Further flow cytometry confirmed significant down-regulation of SOX10 protein, which indicated the SOX10 gene mutation was responsible for the pathogenesis of WS2 patients. In addition, we speculated that some other mutated genes might be related to disease phenotype in this family, which might also participate in promoting the progression of WS2. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
40. Overlapping and distinct pRb pathways in the mammalian auditory and vestibular organs
- Author
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Huang, Mingqian, Sage, Cyrille, Tang, Yong, Goo Lee, Sang, Petrillo, Marco, Hinds, Philip W., and Chen, Zheng-Yi
- Abstract
Retinoblastoma gene (Rb1) is required for proper cell cycle exit in the developing mouse inner ear and its deletion in the embryo leads to proliferation of sensory progenitor cells that differentiate into hair cells and supporting cells. In a conditional hair cell Rb1 knockout mouse,Pou4f3-Cre-pRb-/-, pRb-/-utricular hair cells differentiate and survive into adulthood whereas differentiation and survival of pRb-/-cochlear hair cells are impaired. To comprehensively survey the pRb pathway in the mammalian inner ear, we performed microarray analysis of pRb-/-cochlea and utricle. The comparative analysis shows that the core pathway shared between pRb-/-cochlea and utricle is centered on E2F, the key pathway that mediates pRb function. A majority of differentially expressed genes and enriched pathways are not shared but uniquely associated with pRb-/-cochlea or utricle. In pRb-/-cochlea, pathways involved in early inner ear development such as Wnt/β-catenin and Notch were enriched, whereas pathways involving in proliferation and survival are enriched in pRb-/-utricle. Clustering analysis showed that the pRb-/-inner ear has characteristics of a younger control inner ear, an indication of delayed differentiation. We created a transgenic mouse model (ER-Cre-pRbflox/flox) in which Rb1 can be acutely deleted postnatally. Acute Rb1 deletion in the adult mouse fails to induce proliferation or cell death in inner ear, strongly indicating that Rb1 loss in these postmitotic tissues can be effectively compensated for, or that pRb-mediated changes in the postmitotic compartment result in events that are functionally irreversible once enacted. This study thus supports the concept that pRb-regulated pathways relevant to hair cell development, encompassing proliferation, differentiation and survival, act predominantly during early development.
- Published
- 2011
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41. Cell-Based Therapy Restores Olfactory Function in an Inducible Model of Hyposmia
- Author
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Sarah Kurtenbach, Garrett M. Goss, Stefania Goncalves, Rhea Choi, Joshua M. Hare, Nirupa Chaudhari, and Bradley J. Goldstein
- Subjects
Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Summary: Stem cell-based therapies have been proposed as a strategy to replace damaged tissues, especially in the nervous system. A primary sensory modality, olfaction, is impaired in 12% of the US population, but lacks treatment options. We report here the development of a novel mouse model of inducible hyposmia and demonstrate that purified tissue-specific stem cells delivered intranasally engraft to produce olfactory neurons, achieving recovery of function. Adult mice were rendered hyposmic by conditional deletion of the ciliopathy-related IFT88 gene in the olfactory sensory neuron lineage and following experimentally induced olfactory injury, received either vehicle or stem cell infusion intranasally. Engraftment-derived olfactory neurons were identified histologically, and functional improvements were measured via electrophysiology and behavioral assay. We further explored mechanisms in culture that promote expansion of engraftment-competent adult olfactory basal progenitor cells. These findings provide a basis for translational research on propagating adult tissue-specific sensory progenitor cells and testing their therapeutic potential. : Olfactory sensory losses lack treatment options. The corresponding author and colleagues report the testing of a cellular therapy for olfactory loss. Inducible hyposmia was produced by targeting ciliopathy to the olfactory lineage in mice, and wild-type adult stem cells engrafted to produce functional neurons, assessed using histology, electrophysiology, and behavioral assay. Keywords: olfaction, anosmia, stem cells, neuron, ciliopathy
- Published
- 2019
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42. Directed differentiation and direct reprogramming: Applying stem cell technologies to hearing research.
- Author
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Roccio, Marta
- Subjects
STEM cells ,DEAFNESS ,SENSORY disorders ,COCHLEA ,ANIMAL models in research - Abstract
Hearing loss is the most widely spread sensory disorder in our society. In the majority of cases, it is caused by the loss or malfunctioning of cells in the cochlea: the mechanosensory hair cells, which act as primary sound receptors, and the connecting auditory neurons of the spiral ganglion, which relay the signal to upper brain centers. In contrast to other vertebrates, where damage to the hearing organ can be repaired through the activity of resident cells, acting as tissue progenitors, in mammals, sensory cell damage or loss is irreversible. The understanding of gene and cellular functions, through analysis of different animal models, has helped to identify causes of disease and possible targets for hearing restoration. Translation of these findings to novel therapeutics is, however, hindered by the lack of cellular assays, based on human sensory cells, to evaluate the conservation of molecular pathways across species and the efficacy of novel therapeutic strategies. In the last decade, stem cell technologies enabled to generate human sensory cell types in vitro, providing novel tools to study human inner ear biology, model disease, and validate therapeutics. This review focuses specifically on two technologies: directed differentiation of pluripotent stem cells and direct reprogramming of somatic cell types to sensory hair cells and neurons. Recent development in the field are discussed as well as how these tools could be implemented to become routinely adopted experimental models for hearing research. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
43. Mosaic CRISPR-stop enables rapid phenotyping of nonsense mutations in essential genes.
- Author
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Guangqin Wang, Chao Li, Shunji He, and Zhiyong Liu
- Subjects
NONSENSE mutation ,HAIR cells ,LETHAL mutations ,INNER ear ,GENETIC mutation ,GENETIC testing - Abstract
CRISPR-stop converts protein-coding sequences into stop codons, which, in the appropriate location, results in a null allele. CRISPRstop induction in one-cell-stage zygotes generates Founder 0 (F0) mice that are homozygous mutants; this avoids mouse breeding and serves as a rapid screening approach for nonlethal genes. However, loss of function of 25% of mammalian genes causes early lethality. Here, we induced CRISPR-stop in one of the two blastomeres of the zygote, a method we name mosaic CRISPR-stop, to produce mosaic Atoh1 and Sox10 F0 mice; these mice not only survived longer than regular Atoh1/Sox10 knockout mice but also displayed their recognized cochlear phenotypes. Moreover, by using mosaic CRISPR-stop, we uncovered a previously unknown role of another lethal gene, Rbm24, in the survival of cochlear outer hair cells (OHCs), and we further validated the importance of Rbm24 in OHCs by using our Rbm24 conditional knockout model. Together, our results demonstrated that mosaic CRISPR-stop is reliable and rapid, and we believe this method will facilitate rapid genetic screening of developmentally lethal genes in the mouse inner ear and also in other organs. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
44. FGF20‐FGFR1 signaling through MAPK and PI3K controls sensory progenitor differentiation in the organ of Corti.
- Author
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Su, Yutao, Yang, Lu M., and Ornitz, David M.
- Subjects
CORTI'S organ ,PHOSPHATIDYLINOSITOL 3-kinases ,HAIR cells ,MITOGEN-activated protein kinases ,PTEN protein - Abstract
Background: Fibroblast Growth Factor 20 (FGF20)‐FGF receptor 1 (FGFR1) signaling is essential for cochlear hair cell (HC) and supporting cell (SC) differentiation. In other organ systems, FGFR1 signals through several intracellular pathways including MAPK (ERK), PI3K, phospholipase C ɣ (PLCɣ), and p38. Previous studies implicated MAPK and PI3K pathways in HC and SC development. We hypothesized that one or both would be important downstream mediators of FGF20‐FGFR1 signaling for HC differentiation. Results: By inhibiting pathways downstream of FGFR1 in cochlea explant cultures, we established that both MAPK and PI3K pathways are required for HC differentiation while PLCɣ and p38 pathways are not. Examining the canonical PI3K pathway, we found that while AKT is necessary for HC differentiation, it is not sufficient to rescue the Fgf20−/− phenotype. To determine whether PI3K functions downstream of FGF20, we inhibited Phosphatase and Tensin Homolog (PTEN) in Fgf20−/− explants. Overactivation of PI3K resulted in a partial rescue of the Fgf20−/− phenotype, demonstrating a requirement for PI3K downstream of FGF20. Consistent with a requirement for the MAPK pathway for FGF20‐regulated HC differentiation, we show that treating Fgf20−/− explants with FGF9 increased levels of dpERK. Conclusions: Together, these data provide evidence that both MAPK and PI3K are important downstream mediators of FGF20‐FGFR1 signaling during HC and SC differentiation. Key Findings: PI3K and MEK1/2 are necessary for hair cell differentiation while p38 and PLCγ are not.pAKT is necessary but not sufficient for hair cell differentiation.PTEN inhibition partially rescues Fgf20 knockout phenotype.dpERK is downstream of FGF20‐FGFR1 signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
45. Research Progress of Hair Cell Protection Mechanism.
- Author
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Mu, Yurong, Su, Hongguo, Wu, Fan, Yang, Jianming, and Li, Dan
- Subjects
HAIR cells ,HEARING disorders ,APOPTOSIS ,PROGRESS - Abstract
How to prevent and treat hearing-related diseases through the protection of hair cells (HCs) is the focus in the field of hearing in recent years. Hearing loss caused by dysfunction or loss of HCs is the main cause of hearing diseases. Therefore, clarifying the related mechanisms of HC development, apoptosis, protection, and regeneration is the main goal of current hearing research. This review introduces the latest research on mechanism of HC protection and regeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
46. Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty.
- Author
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Kalra, Gurmannat, Milon, Beatrice, Casella, Alex M., Herb, Brian R., Humphries, Elizabeth, Song, Yang, Rose, Kevin P., Hertzano, Ronna, and Ament, Seth A.
- Subjects
HAIR cells ,COCHLEA physiology ,HUMAN genome ,EPITHELIAL cells ,GENETIC regulation ,RISK assessment ,HEARING disorders - Abstract
Age-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a meta-analysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 330,759) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5x10
-8 ), of which eight have not been reported previously in the peer-reviewed literature. We investigated the regulatory and cell specific expression for these loci by generating mRNA-seq, ATAC-seq, and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were most strongly enriched for expression in cochlear epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in sensory epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type non-specific regulatory regions. Epigenomic and statistical fine-mapping most strongly supported 50 putative risk genes. Of these, 39 were expressed robustly in mouse cochlea and 16 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium. Author summary: The genetic architecture of age-related hearing impairment (ARHI), a strongly heritable condition, has not been well studied. We present a systems genetics analysis of risk loci for ARHI. We performed a joint GWAS analysis of four hearing related traits from the UK Biobank and identified 31 genome-wide significant risk loci for hearing difficulty, eight of which have not been previously reported. By integrating these risk loci with transcriptomic and epigenomic data from the mouse cochlea, we discovered that risk loci are strongly enriched at genes and open chromatin regions that are active in cochlear sensory epithelial cells. Our results suggest an important role in ARHI for altered gene regulation in cochlear hair cells and supporting cells. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
47. Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals.
- Author
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Waqas, Muhammad, Us-Salam, Iram, Bibi, Zainab, Wang, Yunfeng, Li, He, Zhu, Zhongshou, and He, Shuangba
- Subjects
SENSORINEURAL hearing loss ,HAIR cells ,HEARING aids ,HUMAN stem cells ,STEM cells - Abstract
The hair cells that reside in the cochlear sensory epithelium are the fundamental sensory structures responsible for understanding the mechanical sound waves evoked in the environment. The intense damage to these sensory structures may result in permanent hearing loss. The present strategies to rehabilitate the hearing function include either hearing aids or cochlear implants that may recover the hearing capability of deaf patients to a limited extent. Therefore, much attention has been paid on developing regenerative therapies to regenerate/replace the lost hair cells to treat the damaged cochlear sensory epithelium. The stem cell therapy is a promising approach to develop the functional hair cells and neuronal cells from endogenous and exogenous stem cell pool to recover hearing loss. In this review, we specifically discuss the potential of different kinds of stem cells that hold the potential to restore sensorineural hearing loss in mammals and comprehensively explain the current therapeutic applications of stem cells in both the human and mouse inner ear to regenerate/replace the lost hair cells and spiral ganglion neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
48. Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal.
- Author
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Gnedeva, Ksenia, Xizi Wang, McGovern, Melissa M., Barton, Matthew, Litao Tao, Trecek, Talon, Monroe, Tanner O., Llamas, Juan, Makmura, Welly, Martin, James F., Groves, Andrew K., Warchol, Mark, and Segil, Neil
- Subjects
CORTI'S organ ,SENSORY receptors ,INNER ear ,HAIR cells ,CELL cycle - Abstract
Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium--the organ of Corti--progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
49. Historical Aspects of Gene Therapy and Stem Cell Therapy in the Treatment of Hearing and Balance Disorder.
- Author
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Van De Water, Thomas R.
- Published
- 2020
- Full Text
- View/download PDF
50. Fate‐mapping analysis using Rorb‐IRES‐Cre reveals apical‐to‐basal gradient of Rorb expression in mouse cochlea.
- Author
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Li, Chao, Wang, Yunfeng, Wang, Guangqin, Lu, Ying, He, Shunji, Sun, Yuwei, and Liu, Zhiyong
- Subjects
HAIR cells ,COCHLEA ,INNER ear ,MICE ,PROTEIN expression - Abstract
Background: Conditional loss‐of‐function studies are widely conducted using the Cre/Loxp system because this helps circumvent embryonic or neonatal lethality problems. However, Cre strains specific to the inner ear are lacking, and thus lethality frequently occurs even in conditional knockout studies. Results: Here, we report a Rorb‐IRES‐Cre knockin mouse strain in which the Cre recapitulates the expression pattern of endogenous Rorb (RAR‐related orphan receptor beta). Analysis of Rorb‐IRES‐Cre/+; Rosa26‐CAG‐LSL‐tdTomato/+ cochlear samples revealed that tdTomato was expressed at the apical turn only by E12.5. TdTomato was observed in the apical and middle turns but was minimally expressed in the basal turn at E15.5, E18.5, and P5. However, most of the auditory hair cells (HCs) and supporting cells (SCs) in all three turns were tdTomato+ at P15 and P30. Intriguingly, no tdTomato+ vestibular cells were detected until P5 and a few cells were present at P15 and P30. Finally, we also confirmed Rorb mRNA and protein expression in cochlear HCs and SCs at P30. Conclusions: We reveal that Rorb expression exhibits an apical‐to‐basal gradient in cochleae. The cochlear‐specific and apical‐to‐basal‐gradient Rorb Cre activity should enable discrimination of gene functions in cochlear vs vestibular regions as well as low‐frequency vs high‐frequency regions in the cochlea. Key Findings: Rorb is turned on in apical to basal gradient in mouse cochlea.Rorb expression is maintained in adult cochlear hair cells and supporting cells.Rorb is not expressed in mouse vestibular organs.Rorb‐IRES‐Cre is a suitable tool for conditional loss‐and‐gain of function studies in mouse inner ear. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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