1. Exosomes mediate sensory hair cell protection in the inner ear.
- Author
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Breglio AM, May LA, Barzik M, Welsh NC, Francis SP, Costain TQ, Wang L, Anderson DE, Petralia RS, Wang YX, Friedman TB, Wood MJ, and Cunningham LL
- Subjects
- Animals, Anti-Bacterial Agents toxicity, Cell Communication drug effects, Cell Communication physiology, Cell Survival drug effects, Female, HSP70 Heat-Shock Proteins genetics, HSP70 Heat-Shock Proteins metabolism, Hair Cells, Auditory drug effects, Hair Cells, Auditory pathology, Heat-Shock Response physiology, In Vitro Techniques, Mice, Mice, Inbred CBA, Mice, Knockout, Models, Biological, Neomycin toxicity, Ototoxicity genetics, Ototoxicity metabolism, Ototoxicity pathology, Pregnancy, Toll-Like Receptor 4 metabolism, Up-Regulation, Exosomes metabolism, Hair Cells, Auditory metabolism
- Abstract
Hair cells, the mechanosensory receptors of the inner ear, are responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular heat shock 70-kDa protein (HSP70). We investigated the mechanisms underlying this non-cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, whereas inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair cell-specific expression of the known HSP70 receptor TLR4 was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate nonautonomous hair cell survival. Exosomes may hold potential as nanocarriers for delivery of therapeutics against hearing loss.
- Published
- 2020
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