Correa, D. M. | bioRxiv Science

bioRxiv2026

Disruption of a Structural Niche for Otoconia Maintenance May Underlie Common Vestibular Disorders

Many falls and balance disorders in older adults originate in the otolith organs, the gravity sensors of the inner ear. These sensors maintain upright posture through otoconia, calcium carbonate crystals that mass-load the sensory maculae. Otoconia dislodgement causes the most common form of vertigo, and their age-related loss reduces gravity sensation and undermines balance. Yet the cellular mechanisms of otoconia formation and maintenance -and how they fail in disease- remain unknown. Using mineral-preserving histology, crystal-sensitive imaging, volume electron microscopy, and immunolabeling in human and animal otolith organs, we found otoconia biogenesis-related proteins and early crystallization at the pole opposing the macula, the roof domain. We discovered filigree extracellular matrix scaffolds bridging roof and macula, loaded with nascent otoconia, suggesting scaffold-guided transport across the organ. Single-cell transcriptomics nominated a specialized roof mesenchyme, signaling to the roof epithelium, as a driver of otoconia and scaffold production. In guinea pigs with endolymphatic hydrops, fluid expansion of the organs ruptured the otoconia-trafficking scaffolds as roof and macula separated, followed by a decline in macular otoconial mass. We propose a new disease model for common vertigo and balance disorders in which disruption of the otoconia-generating and -trafficking epithelial-mesenchymal roof niche leads to displacement and depletion of otoconia.

neuroscience↗

bioRxiv2025

Hyperplastic Growth, Not Hydrostatic Distension, in Endolymphatic Hydrops in Humans Challenges the Classic View of Meniere's Disease

Menieres disease (MD), a degenerative inner ear disorder, is characterized by debilitating episodic vertigo "attacks" and hearing fluctuations, progressing to permanent sensory impairment. The prevailing dogma attributes these symptoms to an abnormal inner ear fluid buildup--known as endolymphatic hydrops (EH)--with concomitant rise of fluid pressure and repetitive microtrauma to sensory epithelia. However, this pressure-based mechanism lacks direct experimental evidence and fails to explain key clinical aspects of MD--exposing a critical gap in our disease understanding. To revisit the fundamental nature of EH, we performed 3D reconstructive, machine-learning-enhanced histological analyses and immunohistochemistry on human postmortem inner ear specimens. Contrary to the classic theory, EH-affected epithelia showed no signs of pressure-induced change. Instead, we observed an up to four-to seven-fold increase in epithelial cell number (hyperplasia) in both early and advanced EH stages. Quantification of the hyperplastic epithelial surface area, as well as immunohistochemical localization of key fluid homeostasis-associated proteins in the hyperplastic epithelium suggest this epithelial hyperplasia may actively compensate for cell loss in the endolymphatic sac, a key site of MD pathology. These findings challenge the conventional view of EH as solely a pathological pressure phenomenon, instead revealing an unexpected massive cellular expansion of these epithelia, consistent with a coordinated compensatory cellular response aimed at preserving inner ear fluid homeostasis and function in a compromised environment. This paradigm shift introduces dual beneficial and detrimental roles for EH, and suggests new therapeutic avenues for MD focused on promoting compensatory tissue repair while preventing maladaptive remodeling. Significance StatementFor over a century, the leading explanation for Menieres disease--a debilitating inner ear disorder causing vertigo and hearing loss--has been a buildup of fluid and pressure in the inner ear, analogous to conditions like glaucoma. However, this long-held theory has never been directly proven, and treatments based on reducing this supposed pressure have shown limited success. Our research challenges this traditional view, revealing that the expansion of endolymphatic spaces is not primarily a fluid pressure problem, but secondary to a complex cellular response. This fundamental shift in understanding Menieres disease opens new avenues for developing effective therapies to prevent and treat hearing loss and vertigo attacks.

neuroscience↗