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Updated: May 24, 2025
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Exosomes derived from TNF-α preconditioned bone marrow mesenchymal stem cells alleviate cisplatin-induced ototoxicity
Wei Li1, Tao Yang1, Zhiwen Zhang1
1Department of Otolaryngology and Head & Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China.
Abstract:
The polarization of microglia promotes the development of cisplatin-induced ototoxicity, and exosomes (Exo) derived from TNF-α preconditioned mesenchymal stem cells (MSCs) may induce the polarization of macrophage. Mice were intraperitoneally injected with cisplatin to establish the ototoxicity model. Bone marrow MSCs (BMSCs) were preconditioned with TNF-α for 48 h, and the relevant TNF-Exo or Exo was enriched, which were further trans-tympanically administered in the left ear of ototoxic mice. Auditory sensitivity was revealed with auditory brainstem response (ABR) at 8, 16, 24, and 32 kHz. The number of hair cells was detected with Myosin 7a staining. Damaged auditory sensitivity and up-regulated hair cell loss were revealed in cisplatin-exposed mice, which could be reversed by Exo or TNF-Exo treatment. Mechanically, up-regulated Iba1, Cd86, iNOS, Cd206, and Arg1 were detected in cisplatin-exposed cochlea. TNF-Exo or Exo administration further decreased Iba1, Cd86, and iNOS expression, and increased cd206 and Arg1 expression. TNF-Exo or Exo administration inhibited the productin of pro-inflammatory cytokines (IL-1β and IL-6), while enhanced the anti-inflammatory cytokine IL-10 production in the cisplatin-exposed cochlea. Importantly, TNF-Exo administration showed more profound benefits compared with Exo. TNF-α preconditioning might be a new therapeutic option to enhance the capability of BMSCs-derived exosomes against cisplatin-induced ototoxicity.
Insights
Mesenchymal stem cell-derived exosomes (Exo) show potential in treating cisplatin-induced ototoxicity. Preconditioning exosomes with TNF-α (TNF-Exo) enhanced their ability to protect auditory function and hair cells.
Area of Science:
- Ototoxicity research
- Cellular and molecular biology
- Regenerative medicine
Background:
- Cisplatin chemotherapy can cause ototoxicity, damaging auditory function and cochlear hair cells.
- Microglial polarization contributes to cisplatin-induced ototoxicity.
- Exosomes derived from mesenchymal stem cells (MSCs) are being investigated for therapeutic potential.
Purpose of the Study:
- To investigate the therapeutic effects of exosomes derived from TNF-α preconditioned bone marrow MSCs (BMSCs) on cisplatin-induced ototoxicity.
- To explore the underlying mechanisms involving macrophage polarization and cytokine modulation.
Main Methods:
- Ototoxicity was induced in mice using cisplatin.
- Bone marrow MSCs were preconditioned with TNF-α.
- Exosomes (Exo) and TNF-α preconditioned exosomes (TNF-Exo) were administered to ototoxic mice.
- Auditory brainstem response (ABR) and hair cell counts (Myosin 7a staining) were assessed.
- Expression of macrophage markers (Iba1, Cd86, iNOS, Cd206, Arg1) and cytokines (IL-1β, IL-6, IL-10) were analyzed.
Main Results:
- Cisplatin exposure damaged auditory sensitivity and caused hair cell loss.
- Both Exo and TNF-Exo treatments reversed auditory damage and reduced hair cell loss.
- TNF-Exo administration showed more significant protective effects than Exo alone.
- Exosome treatment modulated macrophage polarization, decreasing pro-inflammatory markers and increasing anti-inflammatory markers.
- Exosome treatment reduced pro-inflammatory cytokines (IL-1β, IL-6) and increased anti-inflammatory cytokine (IL-10).
Conclusions:
- TNF-α preconditioning enhances the therapeutic efficacy of BMSCs-derived exosomes against cisplatin-induced ototoxicity.
- MSC-derived exosomes, particularly when preconditioned with TNF-α, represent a promising therapeutic strategy for ototoxicity.
- Modulating macrophage polarization and cytokine balance is a key mechanism of exosome-mediated protection.
