Organoid models advance research into inner ear toxicity

A study from Associate Professor Heiko Locher’s Group at reNEW Leiden, published in Disease Models and Mechanisms, shows that human iPSC-derived inner ear organoids are promising tools to mimic human toxicity in vitro.

Chemotherapy drugs such as cisplatin and antibiotics such as gentamicin frequently cause hearing loss and balance disorders through a process known as ototoxicity. Ototoxicity is usually studied in animal models, but these are not always fully translatable to human physiology and pathology. To overcome this hurdle, the reNEW team used human stem cell-derived inner ear organoids in this study as an alternative. These structures contain the important inner ear sensory cells (hair cells and neurons) that are affected in ototoxicity and allow them to study these effects in a human context.

As expected, the researchers observed toxicity-induced injury in the inner ear organoids after exposure to ototoxic compounds, confirming the value of inner ear organoids to study human ototoxicity and an important milestone for the inner ear research scientific community.

Inner ear organoid with reappearing sensory hair cells after cisplatin-induced injury.
Following prolonged culture, a cisplatin-treated inner ear organoid shows the reappearance of sensory hair cells (yellow) on a layer of supporting cells (cyan), some of which are positive for the proliferation marker Ki-67 (magenta). Image courtesy of Amy W.A. Lucassen.

Strikingly, however, prolonged culture of the treated organoids led to the reappearance of sensory cells. This unexpected finding suggests developmental plasticity and may point to repair and recovery mechanisms in which supporting cells play a crucial role.

“At first, I thought we made a mistake, because the human inner ear is incapable of regeneration,”  said Amy Lucassen, first author of the study. “But we kept seeing the same pattern, suggesting that the supporting cells of the human inner ear might be more interesting than we had realized.”

Together, the study opens new avenues for future research. “We believe our inner ear organoid models can be used as a tool to investigate therapies that protect against the ototoxic effects of various compounds,” said Locher. “In addition, the reappearance of sensory cells suggests it might be possible to stimulate regeneration through targeted intervention in the inner ear. Our model allows us to study this process in detail.”