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 F. Nelson

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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
Issue number1
StatePublished - Jul 9 2019
Externally publishedYes


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

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology


Dive into the research topics of 'Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids'. Together they form a unique fingerprint.

Cite this