Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors
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 replac...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.710159/full |
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| author | Silvia T. Erni Silvia T. Erni Silvia T. Erni Silvia T. Erni John C. Gill Carlotta Palaferri Carlotta Palaferri Carlotta Palaferri Gabriella Fernandes Gabriella Fernandes Gabriella Fernandes Michelle Buri Michelle Buri Michelle Buri Katherine Lazarides Denis Grandgirard Denis Grandgirard Albert S. B. Edge Albert S. B. Edge Albert S. B. Edge Stephen L. Leib Stephen L. Leib Marta Roccio Marta Roccio Marta Roccio Marta Roccio |
| author_facet | Silvia T. Erni Silvia T. Erni Silvia T. Erni Silvia T. Erni John C. Gill Carlotta Palaferri Carlotta Palaferri Carlotta Palaferri Gabriella Fernandes Gabriella Fernandes Gabriella Fernandes Michelle Buri Michelle Buri Michelle Buri Katherine Lazarides Denis Grandgirard Denis Grandgirard Albert S. B. Edge Albert S. B. Edge Albert S. B. Edge Stephen L. Leib Stephen L. Leib Marta Roccio Marta Roccio Marta Roccio Marta Roccio |
| author_sort | Silvia T. Erni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T15:29:07Z |
| format | Article |
| id | doaj.art-a5657b29045d44028d45c274ad89c520 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-22T15:29:07Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-a5657b29045d44028d45c274ad89c5202022-12-21T18:21:25ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-08-01910.3389/fcell.2021.710159710159Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase InhibitorsSilvia T. Erni0Silvia T. Erni1Silvia T. Erni2Silvia T. Erni3John C. Gill4Carlotta Palaferri5Carlotta Palaferri6Carlotta Palaferri7Gabriella Fernandes8Gabriella Fernandes9Gabriella Fernandes10Michelle Buri11Michelle Buri12Michelle Buri13Katherine Lazarides14Denis Grandgirard15Denis Grandgirard16Albert S. B. Edge17Albert S. B. Edge18Albert S. B. Edge19Stephen L. Leib20Stephen L. Leib21Marta Roccio22Marta Roccio23Marta Roccio24Marta Roccio25Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandLaboratory of Inner Ear Research, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandGraduate School for Cellular and Biomedical Sciences, University of Bern, Bern, SwitzerlandAudion Therapeutics B.V., Amsterdam, NetherlandsNeuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandLaboratory of Inner Ear Research, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandNeuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandLaboratory of Inner Ear Research, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandNeuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandLaboratory of Inner Ear Research, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandAudion Therapeutics B.V., Amsterdam, NetherlandsNeuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandMassachusetts Eye and Ear, Boston, MA, United StatesHarvard Medical School, Boston, MA, United StatesHarvard Stem Cell Institute, Cambridge, MA, United StatesNeuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandCluster for Regenerative Neuroscience, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandLaboratory of Inner Ear Research, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, Zurich, Switzerland0Department of Otorhinolaryngology, University of Zurich, Zurich, SwitzerlandSensorineural 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.710159/fulldrug therapysensorineural hearing losscochlear organoidshair cell regenerationNotch signalinggamma secretase inhibitor |
| spellingShingle | Silvia T. Erni Silvia T. Erni Silvia T. Erni Silvia T. Erni John C. Gill Carlotta Palaferri Carlotta Palaferri Carlotta Palaferri Gabriella Fernandes Gabriella Fernandes Gabriella Fernandes Michelle Buri Michelle Buri Michelle Buri Katherine Lazarides Denis Grandgirard Denis Grandgirard Albert S. B. Edge Albert S. B. Edge Albert S. B. Edge Stephen L. Leib Stephen L. Leib Marta Roccio Marta Roccio Marta Roccio Marta Roccio Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors Frontiers in Cell and Developmental Biology drug therapy sensorineural hearing loss cochlear organoids hair cell regeneration Notch signaling gamma secretase inhibitor |
| title | Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors |
| title_full | Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors |
| title_fullStr | Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors |
| title_full_unstemmed | Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors |
| title_short | Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors |
| title_sort | hair cell generation in cochlear culture models mediated by novel γ secretase inhibitors |
| topic | drug therapy sensorineural hearing loss cochlear organoids hair cell regeneration Notch signaling gamma secretase inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.710159/full |
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