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

## TL;DR

This study uses human stem cell-derived inner ear organoids to model how drugs like cisplatin and gentamicin damage hearing cells and how these cells might recover.

## Contribution

The novel use of hiPSC-derived inner ear organoids to model ototoxicity and demonstrate cellular plasticity in response to drug exposure.

## Key findings

- Cisplatin and gentamicin caused hair cell and neuronal loss and increased apoptosis in inner ear organoids.
- Treated organoids showed recovery with re-emergence of sensory cells and increased Ki-67 expression in SOX10+ cells.
- The organoid model demonstrates potential for studying ototoxicity and testing protective therapies.

## Abstract

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.

Summary: Human induced pluripotent stem cell-derived inner ear organoids model cisplatin and gentamicin ototoxicity, demonstrating drug-induced sensory cell loss, apoptosis and recovery plasticity, offering a human-relevant platform for ototoxicity studies and otoprotective therapy development.