Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle
Abstract Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cel...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53153-0 |
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| author | Tian Wang Tian Yang Amanda Kedaigle Gabriela Pregernig Ryan McCarthy Ben Holmes Xudong Wu Lars Becker Ning Pan Kathy So Leon Chen Jun He Ahmad Mahmoudi Soumya Negi Monika Kowalczyk Tyler Gibson Noah Druckenbrod Alan G. Cheng Joseph Burns |
| author_facet | Tian Wang Tian Yang Amanda Kedaigle Gabriela Pregernig Ryan McCarthy Ben Holmes Xudong Wu Lars Becker Ning Pan Kathy So Leon Chen Jun He Ahmad Mahmoudi Soumya Negi Monika Kowalczyk Tyler Gibson Noah Druckenbrod Alan G. Cheng Joseph Burns |
| author_sort | Tian Wang |
| collection | DOAJ |
| description | Abstract Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cell regeneration, however, these cells fail to fully mature. Here, we profiled mouse utricles at 14 time points, and defined transcriptomes of developing and mature vestibular hair cells. To mimic native hair cells which downregulate endogenous ATOH1 as they mature, we engineered viral vectors carrying the supporting cell promoters GFAP and RLBP1. In utricles damaged ex vivo, both CMV-ATOH1 and GFAP-ATOH1 increased regeneration more effectively than RLBP1-ATOH1, while GFAP-ATOH1 and RLBP1-ATOH1 induced hair cells with more mature transcriptomes. In utricles damaged in vivo, GFAP-ATOH1 induced regeneration of hair cells expressing genes indicative of maturing type II hair cells, and more hair cells with bundles and synapses than untreated organs. Together our results demonstrate the efficacy of spatiotemporal control of ATOH1 overexpression in inner ear hair cell regeneration. |
| format | Article |
| id | doaj-art-503dc5dba4e848548e5f4dec011e0c8f |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-503dc5dba4e848548e5f4dec011e0c8f2025-08-20T02:11:18ZengNature PortfolioNature Communications2041-17232024-10-0115111710.1038/s41467-024-53153-0Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricleTian Wang0Tian Yang1Amanda Kedaigle2Gabriela Pregernig3Ryan McCarthy4Ben Holmes5Xudong Wu6Lars Becker7Ning Pan8Kathy So9Leon Chen10Jun He11Ahmad Mahmoudi12Soumya Negi13Monika Kowalczyk14Tyler Gibson15Noah Druckenbrod16Alan G. Cheng17Joseph Burns18Department of Otolaryngology-Head and Neck Surgery, Stanford University School of MedicineDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDepartment of Otolaryngology-Head and Neck Surgery, Stanford University School of MedicineDepartment of Otolaryngology-Head and Neck Surgery, Stanford University School of MedicineDepartment of Otolaryngology-Head and Neck Surgery, Stanford University School of MedicineDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDecibel TherapeuticsDepartment of Otolaryngology-Head and Neck Surgery, Stanford University School of MedicineDecibel TherapeuticsAbstract Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cell regeneration, however, these cells fail to fully mature. Here, we profiled mouse utricles at 14 time points, and defined transcriptomes of developing and mature vestibular hair cells. To mimic native hair cells which downregulate endogenous ATOH1 as they mature, we engineered viral vectors carrying the supporting cell promoters GFAP and RLBP1. In utricles damaged ex vivo, both CMV-ATOH1 and GFAP-ATOH1 increased regeneration more effectively than RLBP1-ATOH1, while GFAP-ATOH1 and RLBP1-ATOH1 induced hair cells with more mature transcriptomes. In utricles damaged in vivo, GFAP-ATOH1 induced regeneration of hair cells expressing genes indicative of maturing type II hair cells, and more hair cells with bundles and synapses than untreated organs. Together our results demonstrate the efficacy of spatiotemporal control of ATOH1 overexpression in inner ear hair cell regeneration.https://doi.org/10.1038/s41467-024-53153-0 |
| spellingShingle | Tian Wang Tian Yang Amanda Kedaigle Gabriela Pregernig Ryan McCarthy Ben Holmes Xudong Wu Lars Becker Ning Pan Kathy So Leon Chen Jun He Ahmad Mahmoudi Soumya Negi Monika Kowalczyk Tyler Gibson Noah Druckenbrod Alan G. Cheng Joseph Burns Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle Nature Communications |
| title | Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle |
| title_full | Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle |
| title_fullStr | Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle |
| title_full_unstemmed | Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle |
| title_short | Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle |
| title_sort | precise genetic control of atoh1 enhances maturation of regenerated hair cells in the mature mouse utricle |
| url | https://doi.org/10.1038/s41467-024-53153-0 |
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