Abstract
Meniere's disease (MD), a degenerative inner ear disorder, is characterized by debilitating episodic vertigo and hearing fluctuations, progressing to permanent sensory impairment. The prevailing dogma attributes these symptoms to abnormal inner ear fluid buildup-endolymphatic hydrops (EH)-with pressure rise and repetitive microtrauma to sensory epithelia. However, this pressure-based mechanism lacks direct experimental evidence and fails to explain key clinical aspects. To revisit EH, we performed 3D reconstructive, machine-learning-enhanced histological analyses and immunohistochemistry on postmortem human inner ear specimens. Contrary to the classic pressure-based theory, EH-affected epithelia showed neither increased spacing between neighboring cells nor morphological evidence of ruptures; instead, they exhibited a 4-7-fold increase in epithelial cell number (hyperplasia) in Reissner's and saccular membranes, present in both early and advanced EH. Quantification of hyperplastic epithelial surface area and immunolocalization of fluid homeostasis-associated proteins suggest this hyperplasia may compensate for cell loss in the endolymphatic sac, a key MD site. These findings challenge the view of EH as purely a pressure phenomenon, revealing epithelial expansion consistent with a coordinated compensatory response to preserve fluid homeostasis and function. This paradigm shift introduces dual beneficial and detrimental roles for EH, suggesting new therapies that promote tissue repair while preventing maladaptive remodeling.