Revealing heterogeneity and damage response in the adult human utricle

The human utricle is a vestibular organ composed of sensory and non-sensory cells responsible for maintaining balance. Balance sense gradually deteriorates with age. With the aging population expected to double to 2 billion by 2050, vestibular disorders will pose a significant challenge as no pharmaceutical or biological treatments are available, a current unmet medical need. Here we show, for the first time, the cellular and transcriptional profile 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 cell types, including a unique population, demonstrating the heterogeneity and complexity 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. Our results will serve as a foundation for preclinical studies, paving the way to therapeutic strategies for balance recovery. Overall design: We cultured six whole organotypic utricles for 24 h, three with vehicle control and three treated with gentamicin to induce hair cell damage. Then, we isolated the sensory epithelium and performed bulk RNA-seq.