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

IF 2.3 4区医学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of Neuroscience Methods Pub Date : 2026-06-01 Epub Date: 2026-02-12 DOI:10.1016/j.jneumeth.2026.110709

Bailey H. Duhon , Melanie Fisher , Han TN. Nguyen , Matthew T. Rocco , Eric C. Bielefeld , Yin Ren

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引用次数: 0

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 Nf2^-/- Schwann 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.

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原位前庭神经鞘瘤小鼠模型研究肿瘤-宿主相互作用及感音神经性听力损失机制

感音神经性听力损失（SNHL）是前庭神经鞘瘤（VS）最常见的症状，由肿瘤与宿主的多因素相互作用引起，包括机械性耳蜗前庭神经压迫和耳毒性肿瘤分泌，但其潜在机制尚未完全确定。本研究建立了一个解剖学精确的小鼠模型，并探讨了血迷宫屏障（BLB）破坏在vs相关SNHL中的作用。新方法采用神经耳科学外科技术，采用外侧半规管开窗的岩石切开术，将小鼠Nf2-/-雪旺细胞和患者源性原代VS细胞植入内耳道（IAC）内的耳蜗前庭神经。通过MRI和生物发光评估肿瘤生长情况，通过听脑干反应和行为分析评估听觉和前庭功能。在肿瘤、脑干和耳蜗中进行炎症、基质重塑和紧密连接标志物的免疫荧光检测。结果vs异体移植物从IAC向桥小脑角进展，呈现混合Antoni A/B结构。术后听觉和前庭功能得以保留，但随着肿瘤的生长而逐渐下降。肿瘤、脑干和耳蜗前庭神经均可见巨噬细胞/小胶质细胞活化。基质金属蛋白酶9 （MMP-9）和高迁移率组盒1 （HMGB1）在肿瘤和同侧耳蜗中的过表达与BLB破坏的证据相关，其特征是紧密连接下调和血管纹明显的血管紊乱。现有的动物模型要么需要几个月的时间来建立，要么不能再现先天VS的进展和听力下降。结论：该新型小鼠模型再现了IAC内的天然VS进展，为研究VS相关SNHL的机制提供了一个强大的平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neuroscience Methods 医学-神经科学

CiteScore

7.10

自引率

3.30%

发文量

226

审稿时长

52 days

期刊介绍： The Journal of Neuroscience Methods publishes papers that describe new methods that are specifically for neuroscience research conducted in invertebrates, vertebrates or in man. Major methodological improvements or important refinements of established neuroscience methods are also considered for publication. The Journal''s Scope includes all aspects of contemporary neuroscience research, including anatomical, behavioural, biochemical, cellular, computational, molecular, invasive and non-invasive imaging, optogenetic, and physiological research investigations.