Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss

Cell Rep. 2017 Jan 3;18(1):68-81. doi: 10.1016/j.celrep.2016.12.020.


Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to "degenerative cochlear disease" and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.

Keywords: Pendred syndrome; disease-specific iPS cells; inner ear; outer sulcus cells.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Cell Line
  • Child
  • Child, Preschool
  • Cochlea / pathology*
  • Female
  • Goiter, Nodular / genetics
  • Goiter, Nodular / pathology
  • Goiter, Nodular / therapy
  • Hearing Loss / congenital*
  • Hearing Loss / pathology
  • Hearing Loss / therapy*
  • Hearing Loss, Sensorineural / genetics
  • Hearing Loss, Sensorineural / pathology
  • Hearing Loss, Sensorineural / therapy
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Infant, Newborn
  • Ion Exchange
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / metabolism
  • Metformin / pharmacology
  • Phenotype
  • Protein Aggregates / drug effects
  • Sirolimus / pharmacology
  • Sulfate Transporters
  • Vestibular Aqueduct / abnormalities
  • Vestibular Aqueduct / pathology


  • Membrane Transport Proteins
  • Protein Aggregates
  • SLC26A4 protein, human
  • Sulfate Transporters
  • Metformin
  • Sirolimus

Supplementary concepts

  • Deafness, Autosomal Recessive 4
  • Pendred syndrome