Journal Club: Cells in the human utricles respond by down-regulating E-cadherin after treatment with gentamicin.

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Today's journal article

Boschian C, Forge A, Lovett M, Gale JE, Jagger DJ. Transcriptomic change in human utricles after aminoglycoside-induced hair cell ablation: Dynamic alterations to hair cell and supporting cell genes. 

Why I picked this article

When it comes to inner ear organs, like the cochlea and the vestibular system, our access to human tissue is limited, and hence our understanding of cells in the inner ear in humans is very limited. This research contributes to our understanding of cells in the human vestibular system. 

Aminoglycoside antibiotics are effective drugs for treating infections. Unfortunately, they can also harm auditory and vestibular hair cells in the inner ear, causing permanent hearing and balance problems in mammals. Damage is usually permanent, as, unlike birds or fish, hair cells in mature humans have almost no hair-cell regeneration. In human and other mammals, vestibular cells retain regenerative capacity longer after inner ear hair cells finish developing. 

This research uses human vestibular tissue (from the part called the utricle) that has been damaged by the aminoglycoside antibiotic and uses molecular biology techniques to understand how remaining vestibular cells respond at the molecular level to the insult. Researchers also ask if remaining cells show any molecular signs of repair or regeneration. 

Some of the research findings

Model and approach
  • Tissue: human utricle explants; gentamicin used to ablate hair cells.
  • Data: publicly available bulk RNA-seq: NCBI Gene Expression Omnibus (GEO) portal (GSE109320)
  • Age of donor: between 17 and 81 (mean 50.6, median 51)
  • Donors were undergoing excision of a vestibular schwannoma.
    • 3 untreated samples
    • 4 treated with gentamicin for 48 hours and collected after 3 days, 8 days, 14 days or 18 days in culture. 
    • 2 treated with gentamicin for 48 hours followed by ATOH1-GFP expression in culture.
  • RNASeq (Illumina HiSeq2000)
Finding: 
  • Principal component analysis showed a clearly different RNA profile for gentamicin-treated utricles compared to control. 
  • Hair-cell markers: three hair cell-genes were reduced (PAWR, TMEM183A, SLC8A2) while six genes were increased (up-regulated); FN3K, TTC21A, RAB36, BBS1, MORN1, WDR19.
  • Supporting cell genes: five genes were up-regulated (STX3, ATRN, PARVA, ACSS3, RAB8B). Adherens junction genes: significant shifts; E-cadherin (CDH1) down-regulated, consistent with junction loosening during lesion sealing. This was observed in utricles. 
  • This was observed in microscopic analysis of utricles. 
  • Junctional complexes appeared preserved in gentamicin-treated crista ampullaris. 
Part of Figure 3A and B, Junctional complexes in cells of utricle visualised under microscope. AG (aminoglycoside treated). Boschian et al. 2025 

Junction remodelling seems to be the response of cells in the utricle to the gentamicin-induced toxicity.  plasticity. Junctional proteins have been suggested to regulate a cell's ability to differentiate (become different types of cells). So, further understanding this response in utricles and reduction of E-cadherin may help us target this protein for promoting regenerative response. 

Haruna's takeaway

It is interesting to see a particular change in E-cadherins and how vestibular cells seem to respond dynamically over the observed period (2-18 days after gentamicin treatment). 

One thing to highlight is that this study provides very valuable data from human vestibular tissues to an open database accessible to all other researchers. As the majority of molecular biology work in our field of inner ear research, cochlea or vestibular system, comes from animal models, human data are very precious and invaluable. Huge thanks to the donors who were undergoing vestibular schwannoma removal, who kindly donated their inner ear tissue for scientific understanding of the human inner ear.  

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This is Haruna's 56/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.