Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids
Summary: Mutations in the gene encoding the type II transmembrane protease 3 (TMPRSS3) cause human hearing loss, although the underlying mechanisms that result in TMPRSS3-related hearing loss are still unclear. We combined the use of stem cell-derived inner ear organoids with single-cell RNA sequenc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-07-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221367111930181X |
| _version_ | 1819133051017363456 |
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| author | Pei-Ciao Tang Alpha L. Alex Jing Nie Jiyoon Lee Adam A. Roth Kevin T. Booth Karl R. Koehler Eri Hashino Rick F. Nelson |
| author_facet | Pei-Ciao Tang Alpha L. Alex Jing Nie Jiyoon Lee Adam A. Roth Kevin T. Booth Karl R. Koehler Eri Hashino Rick F. Nelson |
| author_sort | Pei-Ciao Tang |
| collection | DOAJ |
| description | Summary: Mutations in the gene encoding the type II transmembrane protease 3 (TMPRSS3) cause human hearing loss, although the underlying mechanisms that result in TMPRSS3-related hearing loss are still unclear. We combined the use of stem cell-derived inner ear organoids with single-cell RNA sequencing to investigate the role of TMPRSS3. Defective Tmprss3 leads to hair cell apoptosis without altering the development of hair cells and the formation of the mechanotransduction apparatus. Prior to degeneration, Tmprss3-KO hair cells demonstrate reduced numbers of BK channels and lower expressions of genes encoding calcium ion-binding proteins, suggesting a disruption in intracellular homeostasis. A proteolytically active TMPRSS3 was detected on cell membranes in addition to ER of cells in inner ear organoids. Our in vitro model recapitulated salient features of genetically associated inner ear abnormalities and will serve as a powerful tool for studying inner ear disorders. : The role of TMPRSS3 in auditory hair cell (HC) remains unclear. Nelson and colleagues generated stem cell-derived inner ear organoids with Tmprss3 mutations, which demonstrate that (1) inner ear organoids exhibit comparative effects of the genetic abnormality to its in vivo counterparts, (2) Tmprss3 mutations lead to HC apoptosis and reduced BK channels, and (3) TMPRSS3 localizes to the cell membrane. Keywords: deafness, degeneration, disease modeling, embryonic stem cell, hair cell, inner ear, organoid, TMPRSS3, vestibular system |
| first_indexed | 2024-12-22T09:41:08Z |
| format | Article |
| id | doaj.art-0b32ffcd58a04aa0900f1c6271a2373f |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-22T09:41:08Z |
| publishDate | 2019-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-0b32ffcd58a04aa0900f1c6271a2373f2022-12-21T18:30:40ZengElsevierStem Cell Reports2213-67112019-07-01131147162Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear OrganoidsPei-Ciao Tang0Alpha L. Alex1Jing Nie2Jiyoon Lee3Adam A. Roth4Kevin T. Booth5Karl R. Koehler6Eri Hashino7Rick F. Nelson8Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USAMolecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; Corresponding authorSummary: Mutations in the gene encoding the type II transmembrane protease 3 (TMPRSS3) cause human hearing loss, although the underlying mechanisms that result in TMPRSS3-related hearing loss are still unclear. We combined the use of stem cell-derived inner ear organoids with single-cell RNA sequencing to investigate the role of TMPRSS3. Defective Tmprss3 leads to hair cell apoptosis without altering the development of hair cells and the formation of the mechanotransduction apparatus. Prior to degeneration, Tmprss3-KO hair cells demonstrate reduced numbers of BK channels and lower expressions of genes encoding calcium ion-binding proteins, suggesting a disruption in intracellular homeostasis. A proteolytically active TMPRSS3 was detected on cell membranes in addition to ER of cells in inner ear organoids. Our in vitro model recapitulated salient features of genetically associated inner ear abnormalities and will serve as a powerful tool for studying inner ear disorders. : The role of TMPRSS3 in auditory hair cell (HC) remains unclear. Nelson and colleagues generated stem cell-derived inner ear organoids with Tmprss3 mutations, which demonstrate that (1) inner ear organoids exhibit comparative effects of the genetic abnormality to its in vivo counterparts, (2) Tmprss3 mutations lead to HC apoptosis and reduced BK channels, and (3) TMPRSS3 localizes to the cell membrane. Keywords: deafness, degeneration, disease modeling, embryonic stem cell, hair cell, inner ear, organoid, TMPRSS3, vestibular systemhttp://www.sciencedirect.com/science/article/pii/S221367111930181X |
| spellingShingle | Pei-Ciao Tang Alpha L. Alex Jing Nie Jiyoon Lee Adam A. Roth Kevin T. Booth Karl R. Koehler Eri Hashino Rick F. Nelson Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids Stem Cell Reports |
| title | Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids |
| title_full | Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids |
| title_fullStr | Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids |
| title_full_unstemmed | Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids |
| title_short | Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids |
| title_sort | defective tmprss3 associated hair cell degeneration in inner ear organoids |
| url | http://www.sciencedirect.com/science/article/pii/S221367111930181X |
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