Key Takeaways & Executive Findings
- •• Intratympanic injection of hucMSC-EXOs effectively delivers exosomes to vestibular end organs, including utricle, saccule, and crista ampullaris. • hucMSC-EXOs significantly attenuate gentamicin-induced vestibular dysfunction and hearing loss, outperforming dexamethasone in some behavioral tests. • Exosome treatment reduces hair cell loss in key vestibular regions and modulates apoptosis and autophagy via the SNARE pathway. • Findings support hucMSC-EXOs as a promising therapeutic strategy for gentamicin-induced ototoxicity.
Abstract
Objective To investigate the delivery efficiency of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-EXOs) via intratympanic injection into vestibular end organs, evaluate their protective effects against gentamicin-induced vestibular dysfunction and hearing loss on gentamicin-induced vestibular dysfunction and hearing loss, and explore their regulatory mechanisms on hair cell apoptosis and autophagy. Methods Exosome characteristics were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. PKH26 labeling was used to trace their distribution in the vestibule. SD rats were randomly divided into four groups: control group, gentamicin group (GEN group), gentamicin + exosome group (GEN + EXO group), and gentamicin + dexamethasone group (GEN + DEX group). On day 6 after administration, vestibular function was assessed via open-field test and beam balance test. On day 7, high-frequency hearing (32 kHz) was detected by auditory brainstem response (ABR). The quantity and structural changes of hair cells were analyzed by immunofluorescence staining and scanning electron microscopy. Proteomics was used to analyze differentially expressed proteins in vestibular tissues treated with dexamethasone or hucMSC-EXOs. The regulatory effects on Caspase-3 (apoptosis) and LC3 (autophagy) were validated by immunofluorescence. Results hucMSC-EXOs administered via intratympanic injection were found to target the utricle, saccule, and crista ampullaris. Behavioral studies showed that the GEN + EXO group exhibited significant suppression of gentamicin-induced reduction in total movement distance (p < 0.05) and movement speed (p < 0.05, superior to the GEN + DEX group), with a 60.5% reduction in beam balance test passage time (p < 0.05). ABR results revealed that the auditory threshold at 32 kHz in the GEN + EXO group was 18.3 dB SPL lower than that in the injury group (p < 0.01), with no statistical difference compared to the GEN + DEX group. Hair cell counting showed significant protective effects of exosomes in reducing hair cell loss in the utricular striola (+25%), saccular striola (+44%), and central crista ampullaris
1. Introduction
Gentamicin, an aminoglycoside antibiotic, is widely used in the treatment of severe bacterial infections [1]. However, its clinical use is often complicated by ototoxicity, particularly causing damage to vestibular and auditory hair cells in the inner ear [2, 3]. Studies have shown that gentamicin enters hair cells, leading to abnormal elevation of intracellular calcium concentrations and triggering oxidative stress responses [4]. Additionally, gentamicin induces mitochondrial dysfunction, increases the production of reactive oxygen species (ROS), and ultimately leads to cell death [5]. These complex biological mechanisms severely affect vestibular hair cells, causing symptoms such as vertigo and balance disorders in patients [6]. Currently, therapeutic options for gentamicin-induced vestibular hair cell injury remain relatively limited, with main strategies including early discontinuation of gentamicin and the use of protective agents such as antioxidants and neurotrophic factors [7]. Although some drugs have demonstrated protective effects on hair cells in research, no effective clinical treatment protocols have been established, making the development of novel interventions imperative.
In recent years, umbilical cord mesenchymal stem cells (UC-MSCs) have garnered extensive attention from researchers due to their excellent proliferation and differentiation capabilities, as well as superior immunomodulatory and tissue repair functions [8]. Beyond their own proliferation and differentiation potential, stem cells secrete extracellular vesicles containing various cytokines, which play critical roles in cell protection, regeneration, and repair of damaged tissues [9]. Existing studies have shown that UC-MSCs and their secreted exosomes can protect hair cells through multiple mechanisms, such as anti-apoptosis and promotion of autophagy [10]. Therefore, utilizing UC-MSC-derived exosomes represents a novel and promising approach for treating gentamicin-induced vestibular hair cell injury.
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Runnan Han, Ning Yu, GuoWei Qi, Jing Wang, Yanan Wu, Chuan Qin, Lin Shi, Liang Wang (2026). Mesenchymal stem cell-derived exosomes ameliorate gentamicin-induced vestibular hair cell injury by regulating the SNARE pathway and enhancing autophagy. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04819-z
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-EXOs) delivered via intratympanic injection effectively protect vestibular hair cells from gentamicin-induced damage by regulating the SNARE pathway and enhancing autophagy, thereby reducing vestibular dysfunction and hearing loss.
How were the exosomes administered in the study?
Exosomes were administered via intratympanic injection, which successfully delivered them to the vestibular end organs including the utricle, saccule, and crista ampullaris.
What are the potential clinical implications of this research?
The findings suggest that hucMSC-EXOs could serve as a novel therapeutic strategy for treating gentamicin-induced ototoxicity, potentially offering a more effective and targeted approach compared to current treatments like dexamethasone.
What mechanisms underlie the protective effects of exosomes?
The protective effects are mediated through regulation of the SNARE pathway, which is involved in exocytosis and membrane fusion, and enhancement of autophagy, which helps clear damaged cellular components and reduce apoptosis.
How does this study compare exosome treatment to dexamethasone?
The study found that exosome treatment was superior to dexamethasone in some behavioral tests (e.g., movement speed) and showed comparable effects on hearing threshold recovery, indicating that exosomes may offer a more comprehensive protective effect.
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