Cisplatin exposure damages resident stem cells of the mammalian inner Ear

Authors

  • Eric L. Slattery,

    1. Department of Otolaryngology, Washington University School of Medicine
    Current affiliation:
    1. Michigan Ear Institute, Farmington Hills, MI
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  • Kazuo Oshima,

    1. Department of Otolaryngology – Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
    Current affiliation:
    1. Department of Otorhinolaryngology Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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  • Stefan Heller,

    1. Department of Otolaryngology – Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
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  • Mark E. Warchol

    Corresponding author
    1. Department of Otolaryngology, Washington University School of Medicine
    • Correspondence to: Mark E. Warchol, Department of Otolaryngology, Box 8115, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110. E-mail: warcholm@ent.wustl.edu

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Abstract

Background: Cisplatin is a widely used chemotherapeutic agent that can also cause ototoxic injury. One potential treatment for cisplatin-induced hearing loss involves the activation of endogenous inner ear stem cells, which may then produce replacement hair cells. In this series of experiments, we examined the effects of cisplatin exposure on both hair cells and resident stem cells of the mouse inner ear. Results: Treatment for 24 hr with 10 µM cisplatin caused significant loss of hair cells in the mouse utricle, but such damage was not evident until 4 days after the cisplatin exposure. In addition to killing hair cells, cisplatin treatment also disrupted the actin cytoskeleton in remaining supporting cells, and led to increased histone H2AX phosphorylation within the sensory epithelia. Finally, treatment with 10 µM cisplatin appeared to have direct toxic effects on resident stem cells in the mouse utricle. Exposure to cisplatin blocked the proliferation of isolated stem cells and prevented sphere formation when those cells were maintained in suspension culture. Conclusion: The results suggest that inner ear stem cells may be injured during cisplatin ototoxicity, thus limiting their ability to mediate sensory repair. Developmental Dynamics 243:1328–1337, 2014. © 2014 Wiley Periodicals, Inc.

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