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

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): Makoto Hosoya, Masato Fujioka, Takefumi Sone, Satoshi Okamoto, Wado Akamatsu, Hideki Ukai, Hiroki R. Ueda, Kaoru Ogawa, Tatsuo Matsunaga, Hideyuki Okano
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.

Graphical abstract

Teaser

Hosoya et al. establish an in vitro cochlear cell model derived from Pendred syndrome (PDS)-specific hiPSCs and reveal a degenerative phenotype characterized by intracellular aggregations and increased susceptibilities to cellular stresses. The PDS iPSC model provides an approach for a rational treatment strategy for progressive hearing loss.


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