MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.

microRNA-183 is Essential for Hair Cell Regeneration after Neomycin Injury in Zebrafish

PURPOSE: microRNAs (miRNAs) are non-coding RNAs composed of 20 to 22 nucleotides that regulate development and differentiation in various organs by silencing specific RNAs and regulating gene expression. In the present study, we show that the microRNA (miR)-183 cluster is upregulated during hair cell regeneration and that its inhibition reduces hair cell regeneration following neomycin-induced ototoxicity in zebrafish. MATERIALS AND METHODS: miRNA expression patterns after neomycin exposure were analyzed using microarray chips. Quantitative polymerase chain reaction was performed to validate miR-183 cluster expression patterns following neomycin exposure (500 µM for 2 h). After injection of an antisense morpholino (MO) to miR-183 (MO-183) immediately after fertilization, hair cell regeneration after neomycin exposure in neuromast cells was evaluated by fluorescent staining (YO-PRO1). The MO-183 effect also was assessed in transgenic zebrafish larvae expressing green fluorescent protein (GFP) in inner ear hair cells. RESULTS: Microarray analysis clearly showed that the miR-183 cluster (miR-96, miR-182, and miR-183) was upregulated after neomycin treatment. We also confirmed upregulated expression of the miR-183 cluster during hair cell regeneration after neomycin-induced ototoxicity. miR-183 inhibition using MO-183 reduced hair cell regeneration in both wild-type and GFP transgenic zebrafish larvae. CONCLUSION: Our work demonstrates that the miR-183 cluster is essential for the regeneration of hair cells following ototoxic injury in zebrafish larvae. Therefore, regulation of the miR-183 cluster can be a novel target for stimulation of hair cell regeneration.

effect of local application of neomycin on the spiral ganglion of guinea pig

Eight guinea pigs were used in the present study. Neomycin 1 percent solution was applied to the left ear of six animals, for ten days, after doing perforation of tympanic membrane using diathermy probe. Normal saline was applied to the left ear of the other two animals as control. Three animals were sacrificed ten days following the last application and the other three were sacrificed after 20 days. The cochlea of left side of all animals were processed for electron microscopic study. The spiral ganglion of the animals sacrificed after ten days revealed vacuolation of their cytoplasm, dilation of the cisternae of the endoplasmic reticulum and swelling of the mitochondria with loss of their cristae. In the animal sacrificed after 20 days, marked vacuolation of the cytoplasm of the spiral ganglion cells was evident in addition to irregularity of the nuclear membrane and pyknotic appearance of the nuclei. Also, degeneration of the myelin sheath of myelinated nerve fibers of the spiral ganglion was seen at this stage. The significance of such findings was discussed

Drogas atotóxicas / Ototoxic drugs

Os autores apresentam um levantamento sobre drogas ototóxicas. Relatam quatro casos de lesäo vestibular causada pelo uso de Gentamicina. Discutem a duraçäo dos sintomas e a demora do desaparecimento completo dos mesmos, concluindo que o comprometimento vestibular näo depende somente da dose e do tempo de administraçäo da droga, que o prognóstico näo deve ser sempre otimista em pessoas de idade avançada, que a funçäo renal deve ser sempre observada, que no caso dos medicamentos empregados, a lesäo vestibular näo se acompanha de lesäo auditiva e que o início dos sintomas pode ocorrer dias após cessada a medicaçäo. Finalmente, comentam diversas drogas e a sua açäo no sistema vestibular