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Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Small Extracellular Vesicles Orchestrate Cisplatin-Induced Ototoxicity: Potential Biomarker and Targets Discovery
Jingru Ai1, Shasha Zhang1,2, Mingchen Dai1
1State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
Abstract:
Cisplatin-induced ototoxicity remains a clinical dilemma with limited mechanistic understanding and no food and drug administration (FDA)-approved therapies. Despite emerging roles of small extracellular vesicles (sEV) in drug ototoxicity, their molecular cargo profiles and causal roles to cisplatin-induced ototoxicity are unexplored. This study systematically investigates sEV derived from cochlear explants treated with cisplatin (Cis-sEV) and controls (Ctrl-sEV) using multi-omics profiling. Through small RNA sequencing, 83 differentially expressed microRNAs (miRNAs) are identified in Cis-sEV compared to Ctrl-sEV. Notably, mmu-miR-34a-5p, mmu-miR-140-5p, mmu-miR-15b-5p, mmu-miR-25-3p, and mmu-miR-339-5p are significantly upregulation in Cis-sEVs. Predicted target pathways of these differentially expressed miRNAs are enriched in apoptosis, inflammation, and cellular damage, indicating their potential involvement in cisplatin-induced cochlear damage. LC-MS/MS analysis reveals 90 upregulated and 150 downregulated proteins in Cis-sEV, with many involved in damage response. Specifically, CLTC, CCT2, ANXA6, and HSPA8 are uniquely upregulated proteins in Cis-sEV, and CLTC and ANXA6 are exclusively co-localized in hair cells (HCs) post-cisplatin exposure, suggesting that Cis-sEV originate primarily from damaged HCs. Moreover, CLTC in sEV may serve as a potential biomarker for cisplatin-induced ototoxicity as verified in both in vitro and in vivo models. This study provides novel insights into the molecular mechanisms of cisplatin-induced ototoxicity and identifies potential biomarker and therapeutic targets.
Insights
Small extracellular vesicles (sEVs) carry molecular signals linked to cisplatin ototoxicity. Researchers identified specific microRNAs and proteins in these vesicles, revealing potential biomarkers like CLTC for hearing damage.
Area of Science:
- Oto-toxicology
- Extracellular Vesicle Biology
- Molecular Mechanisms of Drug Damage
Background:
- Cisplatin chemotherapy causes ototoxicity, a significant clinical challenge lacking targeted therapies.
- The role of small extracellular vesicles (sEVs) in drug-induced ototoxicity is poorly understood.
- Mechanistic insights into cisplatin's effects on the cochlea are limited.
Purpose of the Study:
- To investigate the molecular cargo of sEVs from cisplatin-treated cochlear explants.
- To identify potential biomarkers and therapeutic targets for cisplatin-induced ototoxicity.
Main Methods:
- Multi-omics profiling (small RNA sequencing, LC-MS/MS) of sEVs from cisplatin-treated and control cochlear explants.
- Bioinformatic analysis to identify differentially expressed microRNAs (miRNAs) and proteins.
- In vitro and in vivo validation of potential biomarkers.
Main Results:
- 83 differentially expressed miRNAs were identified in cisplatin-derived sEVs (Cis-sEVs), with several linked to apoptosis and cellular damage pathways.
- 90 proteins were upregulated and 150 downregulated in Cis-sEVs, including damage response proteins.
- CLTC and ANXA6 were identified as key proteins in Cis-sEVs, localized to cochlear hair cells, and CLTC showed potential as an ototoxicity biomarker.
Conclusions:
- Cis-sEVs contain specific molecular signatures reflecting cisplatin-induced cochlear damage.
- Upregulated miRNAs and proteins, particularly CLTC, offer insights into ototoxicity mechanisms.
- CLTC in sEVs represents a promising biomarker for monitoring cisplatin-induced ototoxicity.
