Revealing heterogeneity and damage response in the adult human utricle

Abstract The human utricle is a vestibular organ responsible for maintaining balance. Balance function commonly deteriorates with age. With the aging population expected to double to 2 billion by 2050 and no pharmaceutical or biological treatments currently available, balance disorders are a significant unmet medical need. The utricle is composed of sensory and non-sensory cells, which are closely related, and non-sensory cells have a limited capacity to regenerate sensory cells in a damaged balance organ and, therefore, are a relevant therapeutic target. Here, we show the cellular and transcriptional profiles of the adult human utricle and its response to damage by performing bulk and single-cell RNA-sequencing from patient-derived utricles. We discovered six transcriptionally distinct non-sensory cell types, including a novel population, demonstrating the heterogeneity of the adult human utricle. In addition, using an aminoglycoside damage paradigm, we determined the early transcriptional changes of the utricle after damage. Our findings demonstrate that this organ has the capacity to respond to ototoxic damage within 24 h and potentially initiate a regenerative response via an early-responding supporting cell population. This study represents a major step forward in inner ear regenerative medicine, and our results will serve as a foundation for preclinical studies, paving the way to therapeutic strategies for balance recovery.