Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors

Erni, Silvia T.; Gill, John C.; Palaferri, Carlotta; Fernandes, Gabriella; Buri, Michelle; Lazarides, Katherine; Grandgirard, Denis; Edge, Albert S. B.; Leib, Stephen; Roccio, Marta (2021). Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors. Frontiers in cell and developmental biology, 9(2256) Frontiers 10.3389/fcell.2021.710159

[img]
Preview
Text
fcell-09-710159.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (3MB) | Preview

Sensorineural hearing loss is prevalent within society affecting the quality of life of 460 million worldwide. In the majority of cases, this is due to insult or degeneration of mechanosensory hair cells in the cochlea. In adult mammals, hair cell loss is irreversible as sensory cells are not replaced spontaneously. Genetic inhibition of Notch signaling had been shown to induce hair cell formation by transdifferentiation of supporting cells in young postnatal rodents and provided an impetus for targeting Notch pathway with small molecule inhibitors for hearing restoration. Here, the oto-regenerative potential of different γ-secretase inhibitors (GSIs) was evaluated in complementary assay models, including cell lines, organotypic cultures of the organ of Corti and cochlear organoids to characterize two novel GSIs (CPD3 and CPD8). GSI-treatment induced hair cell gene expression in all these models and was effective in increasing hair cell numbers, in particular outer hair cells, both in baseline conditions and in response to ototoxic damage. Hair cells were generated from transdifferentiation of supporting cells. Similar findings were obtained in cochlear organoid cultures, used for the first time to probe regeneration following sisomicin-induced damage. Finally, effective absorption of a novel GSI through the round window membrane and hair cell induction was attained in a whole cochlea culture model and in vivo pharmacokinetic comparisons of transtympanic delivery of GSIs and different vehicle formulations were successfully conducted in guinea pigs. This preclinical evaluation of targeting Notch signaling with novel GSIs illustrates methods of characterization for hearing restoration molecules, enabling translation to more complex animal studies and clinical research.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Forschungsgruppe Audiologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Erni, Silvia Talitha; Palaferri, Carlotta; Fernandes Pires, Gabriella Patrizia; Buri, Michelle; Grandgirard, Denis; Leib, Stephen and Roccio, Marta

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2296-634X

Publisher:

Frontiers

Funders:

[198] Innosuisse - Swiss Innovation Agency ; [4] Swiss National Science Foundation ; [UNSPECIFIED] European Union’s Horizon 2020 Framework Programme under the Eurostars E!10491 HEARit project

Language:

English

Submitter:

Stephen Leib

Date Deposited:

31 Aug 2021 17:29

Last Modified:

31 Aug 2021 17:29

Publisher DOI:

10.3389/fcell.2021.710159

BORIS DOI:

10.48350/158164

URI:

https://boris.unibe.ch/id/eprint/158164

Actions (login required)

Edit item Edit item
Provide Feedback