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Stem Cell Reports. 2019 Jul 9;13(1):147-162. doi: 10.1016/j.stemcr.2019.05.014. Epub 2019 Jun 13.

Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids.

Author information

1
Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
2
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA.
3
Department 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, USA.
4
Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: ricnelso@iupui.edu.

Abstract

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.

KEYWORDS:

TMPRSS3; deafness; degeneration; disease modeling; embryonic stem cell; hair cell; inner ear; organoid; vestibular system

PMID:
31204303
DOI:
10.1016/j.stemcr.2019.05.014
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