Otic Organoids Containing Spiral Ganglion Neuron-like Cells Derived from Human-induced Pluripotent Stem Cells as a Model of Drug-induced Neuropathy

Sho Kurihara, Masato Fujioka, Motoki Hirabayashi, Tomohiko Yoshida, Makoto Hosoya, Masashi Nagase, Fusao Kato, Kaoru Ogawa, Hideyuki Okano, Hiromi Kojima, Hirotaka James Okano

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The spiral ganglion of the cochlea is essential for hearing and contains primary bipolar neurons that relay action potentials generated by mechanosensory hair cells. Injury to spiral ganglion neurons (SGNs) causes permanent hearing loss because these cells have limited regenerative capacity. Establishment of human cell-derived inner ear tissue in vitro could facilitate the development of treatments for hearing loss. Here, we report a stepwise protocol for differentiating human-induced pluripotent stem cells (hiPSCs) into otic organoids that contain SGN-like cells and demonstrate that otic organoids have potential for use as an experimental model of drug-induced neuropathy. Otic progenitor cells (OPCs) were created by 2D culture of hiPSCs for 9 days. Otic spheroids were formed after 2D culture of OPCs for 2 days in a hypoxic environment. Otic organoids were generated by 3D culture of otic spheroids under hypoxic conditions for 5 days and normoxic conditions for a further 30 days or more. The protein expression profile, morphological characteristics, and electrophysiological properties of SGN-like cells in otic organoids were similar to those of primary SGNs. Live-cell imaging of AAV-syn-EGFP-labeled neurons demonstrated temporal changes in cell morphology and revealed the toxic effects of ouabain (which causes SGN-specific damage in animal experiments) and cisplatin (a chemotherapeutic drug with ototoxic adverse effects). Furthermore, a cyclin-dependent kinase-2 inhibitor suppressed the toxic actions of cisplatin on SGN-like cells in otic organoids. The otic organoid described here is a candidate novel drug screening system and could be used to identify drugs for the prevention of cisplatin-induced neuropathy.

Original languageEnglish
Pages (from-to)282-296
Number of pages15
JournalStem Cells Translational Medicine
Volume11
Issue number3
DOIs
Publication statusPublished - 2022 Mar

Keywords

  • drug screening
  • induced pluripotent stem cells
  • inner ear
  • organoid
  • spiral ganglion

ASJC Scopus subject areas

  • Medicine(all)

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