Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids

Pei Ciao Tang, Alpha L. Alex, Jing Nie, Jiyoon Lee, Adam A. Roth, Kevin T. Booth, Karl R. Koehler, Eri Hashino, Rick Nelson

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)147-162
Number of pages16
JournalStem Cell Reports
Volume13
Issue number1
DOIs
StatePublished - Jul 9 2019

Fingerprint

Organoids
Inner Ear
Cells
Large-Conductance Calcium-Activated Potassium Channels
Gene encoding
Audition
Cell membranes
Stem cells
Apoptosis
Hearing Loss
Mutation
Auditory Hair Cells
Stem Cells
Cell Membrane
RNA Sequence Analysis
Carrier Proteins
Calcium-Binding Proteins
Peptide Hydrolases
RNA
Ions

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids. / Tang, Pei Ciao; Alex, Alpha L.; Nie, Jing; Lee, Jiyoon; Roth, Adam A.; Booth, Kevin T.; Koehler, Karl R.; Hashino, Eri; Nelson, Rick.

In: Stem Cell Reports, Vol. 13, No. 1, 09.07.2019, p. 147-162.

Research output: Contribution to journalArticle

Tang, PC, Alex, AL, Nie, J, Lee, J, Roth, AA, Booth, KT, Koehler, KR, Hashino, E & Nelson, R 2019, 'Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids', Stem Cell Reports, vol. 13, no. 1, pp. 147-162. https://doi.org/10.1016/j.stemcr.2019.05.014
Tang, Pei Ciao ; Alex, Alpha L. ; Nie, Jing ; Lee, Jiyoon ; Roth, Adam A. ; Booth, Kevin T. ; Koehler, Karl R. ; Hashino, Eri ; Nelson, Rick. / Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids. In: Stem Cell Reports. 2019 ; Vol. 13, No. 1. pp. 147-162.
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