Human induced pluripotent stem cell-derived inner ear organoids reveal hair cell damage and plasticity after cisplatin and gentamicin exposure.

Ototoxicity is a leading cause of sensory deficits, including hearing loss and balance disorders. Predicting ototoxicity is challenging owing to translatability issues of animal models and limited access to human inner ear tissue. Known ototoxic drugs, such as cisplatin (a chemotherapeutic) and gentamicin (an aminoglycoside antibiotic), cause irreversible damage to sensory hair cells and neurons. Here, we establish human induced pluripotent stem cell (hiPSC)-derived inner ear organoids as an in vitro model for studying ototoxicity. Exposure to cisplatin and gentamicin led to hair cell and neuronal loss, disrupted organoid architecture and increased cell damage, including apoptosis, in a dose-dependent manner. Remarkably, prolonged culture of treated organoids showed re-emergence of otic vesicle structures with sensory hair cells and neurons. SOX10+ otic epithelial cells exhibited increased Ki-67 expression, indicating a potential for developmental plasticity. Our findings demonstrate the value of hiPSC-derived inner ear organoids as a platform for human ototoxicity modeling and provide a basis for testing otoprotective interventions, offering insights into the intrinsic plasticity of developing inner ear cells.