An orthotopic vestibular schwannoma mouse model to study tumor-host interactions and mechanism of sensorineural hearing loss.

Abstract

BACKGROUND: Sensorineural hearing loss (SNHL) is the most common symptom of vestibular schwannoma (VS), arising from multifactorial tumor-host interactions including mechanical cochleovestibular nerve compression and ototoxic tumor secretion, yet underlying mechanisms remain incompletely defined. This study establishes an anatomically precise mouse model and investigates the role of blood-labyrinth barrier (BLB) disruption in VS-associated SNHL. NEW METHOD: Adapting neuro-otologic surgical techniques, a petrosectomy with lateral semicircular canal fenestration was used to implant mouse Nf2Schwann cells and patient-derived primary VS cells into the cochleovestibular nerve within the internal auditory canal (IAC). Tumor growth was assessed by MRI and bioluminescence, while auditory and vestibular functions were evaluated by auditory brainstem response and behavioral assays. Immunofluorescence of inflammatory, matrix-remodeling, and tight junction markers were performed in the tumor, brainstem and cochlea. RESULTS: VS allografts progressed from the IAC to the cerebellopontine angle, exhibiting mixed Antoni A/B architecture. Auditory and vestibular function was preserved postoperatively and progressively declined with tumor growth. Macrophage/microglia activation was observed in the tumor, brainstem and cochleovestibular nerve. Matrix metalloprotease-9 (MMP-9) and high mobility group box 1 (HMGB1) overexpression in the tumor and ipsilateral cochlea was associated with evidence of BLB disruption, characterized by tight junction downregulation and significant vascular disorganization in the stria vascularis. COMPARISON WITH EXISTING METHODS: Existing animal models either require months to develop or fail to recapitulate native VS progression and hearing decline. CONCLUSION: This novel mouse model recapitulates native VS progression within the IAC and offers a powerful platform to investigate mechanisms underlying VS-associated SNHL.