Transcriptomic characterization of dying hair cells in the avian cochlea

Benkafadar, Nesrine; Janesick, Amanda; Scheibinger, Mirko; Ling, Angela H.; Jan, Taha A.; Heller, Stefan

doi:10.1016/j.celrep.2021.108902

Cited by 25 publications

(44 citation statements)

References 98 publications

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“…For example, in 2019, Wang et al used gene expression signatures of druginduced liver injury as input data to train a deep neural network to predict hepatotoxicity based on transcriptomics profiles (166). Multiple studies have characterized the hair cell transcriptome after exposure to aminoglycosides and cisplatin (167)(168)(169)(170). These gene expression profiles could provide input data to train ototoxicity prediction models based on transcriptome signatures for novel compounds.…”

Section: Computational Modelingmentioning

confidence: 99%

Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings

Coffin

Boney²,

Hill

et al. 2021

Front. Neurol.

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Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of drugs is rarely assessed in pre-clinical drug development or during clinical trials, so this debilitating side-effect is often discovered as patients begin to report hearing loss. Furthermore, drug-induced ototoxicity in adults, and particularly in elderly patients, may go unrecognized due to hearing loss from a variety of etiologies because of a lack of baseline assessments immediately prior to novel therapeutic treatment. During the current pandemic, there is an intense effort to identify new drugs or repurpose FDA-approved drugs to treat COVID-19. Several potential COVID-19 therapeutics are known ototoxins, including chloroquine (CQ) and lopinavir-ritonavir, demonstrating the necessity to identify ototoxic potential in existing and novel medicines. Furthermore, several factors are emerging as potentiators of ototoxicity, such as inflammation (a hallmark of COVID-19), genetic polymorphisms, and ototoxic synergy with co-therapeutics, increasing the necessity to evaluate a drug's potential to induce ototoxicity under varying conditions. Here, we review the potential of COVID-19 therapies to induce ototoxicity and factors that may compound their ototoxic effects. We then discuss two models for rapidly detecting the potential for ototoxicity: mammalian auditory cell lines and the larval zebrafish lateral line. These models offer considerable value for pre-clinical drug development, including development of COVID-19 therapies. Finally, we show the validity of in silico screening for ototoxic potential using a computational model that compares structural similarity of compounds of interest with a database of known ototoxins and non-ototoxins. Preclinical screening at in silico, in vitro, and in vivo levels can provide an earlier indication of the potential for ototoxicity and identify the subset of candidate therapeutics for treating COVID-19 that need to be monitored for ototoxicity as for other widely-used clinical therapeutics, like aminoglycosides and cisplatin.

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Section: Computational Modelingmentioning

confidence: 99%

Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings

Coffin

Boney²,

Hill

et al. 2021

Front. Neurol.

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Section: Interferon Response Genes Are Expressed In the Chicken Basilar Papilla After Hair Cell Loss In Vivomentioning

confidence: 99%

“…We recently developed a surgical method to eliminate all hair cells in the chicken basilar papilla by infusing the ototoxic aminoglycoside sisomicin into the inner ear via canalostomy (Benkafadar et al, 2021;Janesick et al, 2021a). This in vivo damage paradigm differs from existing models because it requires only a single application of the ototoxin, and hair cell extrusion happens within 24 hours (Benkafadar et al, 2021;Janesick et al, 2021a), resulting in temporal synchrony of the regenerative response. Forty-eight hours after damage, we dissected the basilar papilla and employed a rapid "cold peeling" method for obtaining pure sensory epithelia, which does not require the application of proteases and time-consuming incubation (Janesick et al, 2021a;Janesick et al, 2021b).…”

Section: Interferon Response Genes Are Expressed In the Chicken Basilar Papilla After Hair Cell Loss In Vivomentioning

confidence: 99%

“…Moreover, bulk RNA-sequencing techniques lack the resolution to distinguish whether up-regulated genes, such as immune genes, emanate from immune cells or oticderived sensory epithelial cells. We recently unveiled a surgical model for local infusion of the ototoxic drug sisomicin in vivo via the posterior semi-circular canal of the chicken ear (Benkafadar et al, 2021;Janesick et al, 2021a --see Supplemental Files section for preprint). This method yields rapid extrusion of hair cells and temporal synchrony of the regenerative response, which is essential for transcriptomic analyses.…”

Section: Introductionmentioning

confidence: 99%

“…Leveraging recent undamaged homeostatic "baseline" single cell data of the avian basilar papilla (Janesick et al, 2021b), we now have a clear roadmap for detecting changes in gene expression occurring after ototoxic insult. We recently utilized the baseline dataset to explore hair cell demise from 12-24 hours after damage (Benkafadar et al, 2021). Our present study aims to investigate the regenerative (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

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Chicken Auditory Supporting Cells Express Interferon Response Genes during Regeneration towards Nascent Sensory Hair CellsIn Vivo

Janesick

Scheibinger

Benkafadar

et al. 2021

Preprint

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The avian hearing organ is the basilar papilla that, in sharp contrast to the mammalian cochlea, can regenerate sensory hair cells and thereby recover from complete deafness within weeks. The mechanisms that trigger, sustain, and terminate the regenerative response in vivo are largely unknown. Here, we profile the changes in gene expression in the chicken basilar papilla after aminoglycoside antibiotic-induced hair cell loss using RNA-sequencing. The most prominent changes in gene expression were linked to the upregulation of interferon response genes which occurred in supporting cells, confirmed by single-cell RNA-sequencing and in situ hybridization. We determined that the JAK/STAT signaling pathway is essential for the interferon gene response in supporting cells, set in motion by hair cell loss. Four days after ototoxic damage, we identified newly regenerated, nascent auditory hair cells that express genes linked to termination of the interferon response. These cells are incipient modified neurons that represent a population of hair cells en route towards obtaining their location-specific and fully functional cell identity. The robust, transient expression of immune-related genes in supporting cells suggests a potential functional involvement of JAK/STAT signaling and interferon in sensory hair cell regeneration.

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