miR-431 secreted by human vestibular schwannomas increases the mammalian inner ear's vulnerability to noise trauma

Takeshi Fujita; Richard Seist; Shyan-Yuan Kao; Vitor Soares; Lorena Panano; Radhika S Khetani; Lukas D Landegger; Shelley Batts; Konstantina M Stankovic

doi:10.3389/fneur.2023.1268359

miR-431 secreted by human vestibular schwannomas increases the mammalian inner ear's vulnerability to noise trauma

Front Neurol. 2023 Oct 9:14:1268359. doi: 10.3389/fneur.2023.1268359. eCollection 2023.

Authors

Affiliations

¹ Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, United States.
² Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
³ Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, United States.
⁴ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States.
⁵ Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA, United States.

Abstract

Introduction: Vestibular schwannoma (VS) is an intracranial tumor that arises on the vestibular branch of cranial nerve VIII and typically presents with sensorineural hearing loss (SNHL). The mechanisms of this SNHL are postulated to involve alterations in the inner ear's microenvironment mediated by the genetic cargo of VS-secreted extracellular vesicles (EVs). We aimed to identify the EV cargo associated with poor hearing and determine whether its delivery caused hearing loss and cochlear damage in a mouse model in vivo.

Methods: VS tissue was collected from routinely resected tumors of patients with good (VS-GH) or poor (VS-PH) pre-surgical hearing measured via pure-tone average and word recognition scores. Next-generation sequencing was performed on RNA isolated from cultured primary human VS cells and EVs from VS-conditioned media, stratified by patients' hearing ability. microRNA expression levels were compared between VS-PH and VS-GH samples to identify differentially expressed candidates for packaging into a synthetic adeno-associated viral vector (Anc80L65). Viral vectors containing candidate microRNA were infused to the semicircular canals of mice to evaluate the effects on hearing, including after noise exposure.

Results: Differentially expressed microRNAs included hsa-miR-431-5p (enriched in VS-PH) and hsa-miR-192-5p (enriched in VS-GH). Newborn mice receiving intracochlear injection of viral vectors over-expressing hsa-miR-431-GFP, hsa-miR-192-GFP, or GFP only (control) had similar hearing 6 weeks post-injection. However, after acoustic trauma, the miR-431 group displayed significantly worse hearing, and greater loss of synaptic ribbons per inner hair cell in the acoustically traumatized cochlear region than the control group.

Conclusion: Our results suggest that miR-431 contributes to VS-associated hearing loss following cochlear stress. Further investigation is needed to determine whether miR-431 is a potential therapeutic target for SNHL.

Keywords: extracellular vesicles; hearing loss; micro RNA; noise trauma; vestibular schwannoma.

Grants and funding

R01 DC015824/DC/NIDCD NIH HHS/United States