{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T17:35:50Z","timestamp":1787420150082,"version":"build-2736575974"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013297","name":"Eurostars","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013297","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>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 \u03b3-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<jats:italic>in vivo<\/jats:italic>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.<\/jats:p>","DOI":"10.3389\/fcell.2021.710159","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T12:00:35Z","timestamp":1628856035000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Hair Cell Generation in Cochlear Culture Models Mediated by Novel \u03b3-Secretase Inhibitors"],"prefix":"10.3389","volume":"9","author":[{"given":"Silvia T.","family":"Erni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Palaferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Buri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Lazarides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Grandgirard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert S. B.","family":"Edge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Leib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Roccio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nrd4252","article-title":"Therapeutic modulation of Notch signalling \u2014 are we there yet?","volume":"13","author":"Andersson","year":"2014","journal-title":"Nat. Rev. Drug. Disc."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0207140","article-title":"Screen for modulators of atonal homolog 1 gene expression using notch pathway-relevant gene transcription based cellular assays.","volume":"13","author":"Asakura","year":"2018","journal-title":"PLoS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1242\/dev.114926","article-title":"Sensory hair cell development and regeneration: similarities and differences.","volume":"142","author":"Atkinson","year":"2015","journal-title":"Development"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2484","DOI":"10.1242\/dev.083113","article-title":"Lgr proteins in epithelial stem cell biology.","volume":"140","author":"Barker","year":"2013","journal-title":"Development"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1126\/science.284.5421.1837","article-title":"Math1: an essential gene for the generation of inner ear hair cells.","volume":"284","author":"Bermingham","year":"1999","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2019.107785","article-title":"Cochlear histopathology in human genetic hearing loss: state of the science and future prospects.","volume":"382","author":"Bommakanti","year":"2019","journal-title":"Hear. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.stemcr.2014.01.008","article-title":"Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea.","volume":"2","author":"Bramhall","year":"2014","journal-title":"Stem Cell Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/nrm.2016.94","article-title":"Notch signalling in context.","volume":"17","author":"Bray","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B9","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms9557","article-title":"Single-cell RNA-Seq resolves cellular complexity in sensory organs from the neonatal inner ear.","volume":"6","author":"Burns","year":"2015","journal-title":"Nat. Commun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"8167","DOI":"10.1073\/pnas.1202774109","article-title":"Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea.","volume":"109","author":"Chai","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B11","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s10162-011-0267-2","article-title":"Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea.","volume":"12","author":"Chai","year":"2011","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1242\/dev.129.10.2495","article-title":"The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination.","volume":"129","author":"Chen","year":"2002","journal-title":"Development"},{"key":"B13","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.heares.2007.06.006","article-title":"The human fetal cochlea can be a source for auditory progenitors\/stem cells isolation.","volume":"233","author":"Chen","year":"2007","journal-title":"Hear. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/cne.902010406","article-title":"Postembryonic production and aging in inner ear hair cells in sharks.","volume":"201","author":"Corwin","year":"1981","journal-title":"J. Comp. Neurol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3911","DOI":"10.1073\/pnas.82.11.3911","article-title":"Perpetual production of hair cells and maturational changes in hair cell ultrastructure accompany postembryonic growth in an amphibian ear.","volume":"82","author":"Corwin","year":"1985","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1126\/science.3381100","article-title":"Regeneration of sensory hair cells after acoustic trauma.","volume":"240","author":"Corwin","year":"1988","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1242\/dev.103036","article-title":"Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo.","volume":"141","author":"Cox","year":"2014","journal-title":"Development"},{"key":"B18","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.devcel.2008.11.008","article-title":"Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti.","volume":"16","author":"Doetzlhofer","year":"2009","journal-title":"Dev. Cell"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1242\/dev.162263","article-title":"Development of the cochlea.","volume":"147","author":"Driver","year":"2020","journal-title":"Development"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00570","article-title":"Anti-inflammatory and oto-protective effect of the small heat shock protein alpha b-crystallin (HspB5) in experimental pneumococcal meningitis.","volume":"10","author":"Erni","year":"2019","journal-title":"Front. Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nrn1828","article-title":"The sensory and motor roles of auditory hair cells.","volume":"7","author":"Fettiplace","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1126\/science.8456284","article-title":"Ultrastructural evidence for hair cell regeneration in the mammalian inner ear.","volume":"259","author":"Forge","year":"1993","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.ejpb.2020.03.005","article-title":"Intratympanic application of poloxamer 407 hydrogels results in sustained N-acetylcysteine delivery to the inner ear.","volume":"150","author":"Gausterer","year":"2020","journal-title":"Eur. J. Pharmaceutics Biopharmaceutics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1242\/dev.067074","article-title":"Shaping sound in space: the regulation of inner ear patterning.","volume":"139","author":"Groves","year":"2012","journal-title":"Development"},{"key":"B25","first-page":"83","article-title":"Targeting \u03b3-secretase in breast cancer.","volume":"4","author":"Han","year":"2012","journal-title":"Breast Cancer: Targets Ther."},{"key":"B26","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.ydbio.2008.01.006","article-title":"Hesr1 and Hesr2 may act as early effectors of Notch signaling in the developing cochlea.","volume":"316","author":"Hayashi","year":"2008","journal-title":"Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.00013","article-title":"Characterizing adult cochlear supporting cell transcriptional diversity using Single-Cell RNA-Seq: validation in the adult mouse and translational implications for the adult human cochlea.","volume":"13","author":"Hoa","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"9479","DOI":"10.1523\/jneurosci.2447-15.2016","article-title":"Diphtheria toxin-induced cell death triggers wnt-dependent hair cell regeneration in neonatal mice.","volume":"36","author":"Hu","year":"2016","journal-title":"J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1172\/jci77424","article-title":"Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.","volume":"125","author":"Huth","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1242\/dev.080358","article-title":"Function for canonical Wnt\/beta-catenin signaling in the developing mammalian cochlea.","volume":"139","author":"Jacques","year":"2012","journal-title":"Development"},{"key":"B31","doi-asserted-by":"crossref","first-page":"918.e6","DOI":"10.1053\/j.gastro.2010.05.081","article-title":"Atonal homolog 1 is required for growth and differentiation effects of Notch\/\u03b3-Secretase inhibitors on normal and cancerous intestinal epithelial cells.","volume":"139","author":"Kazanjian","year":"2010","journal-title":"Gastroenterology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1038\/nrn1987","article-title":"Regulation of cell fate in the sensory epithelia of the inner ear.","volume":"7","author":"Kelley","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.semcdb.2013.04.002","article-title":"Notch signaling during cell fate determination in the inner ear.","volume":"24","author":"Kiernan","year":"2013","journal-title":"Semin. Cell. Dev. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/nbt.3840","article-title":"Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells.","volume":"35","author":"Koehler","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","article-title":"The canonical Notch signaling pathway: unfolding the activation mechanism.","volume":"137","author":"Kopan","year":"2009","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073276","article-title":"Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea.","volume":"8","author":"Korrapati","year":"2013","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1128\/iai.68.2.615-620.2000","article-title":"Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis.","volume":"68","author":"Leib","year":"2000","journal-title":"Infect. Immun."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00014","article-title":"Applications of Lgr5-Positive cochlear progenitors (LCPs) to the study of hair cell differentiation.","volume":"7","author":"Lenz","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1073\/pnas.1415901112","article-title":"Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway.","volume":"112","author":"Li","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B40","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1177\/019262339001800119","article-title":"Quantitative assessment of inner ear pathology following ototoxic drugs or acoustic trauma.","volume":"18","author":"Liberman","year":"1990","journal-title":"Toxicol. Pathol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/s1567-133x(03)00089-9","article-title":"Math1-driven GFP expression in the developing nervous system of transgenic mice.","volume":"3","author":"Lumpkin","year":"2003","journal-title":"Gene Exp. Patterns"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00110","article-title":"Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea.","volume":"9","author":"Maass","year":"2015","journal-title":"Front. Cell Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1016\/j.celrep.2017.01.066","article-title":"Clonal expansion of Lgr5-positive cells from mammalian cochlea and high-purity generation of sensory hair cells.","volume":"18","author":"McLean","year":"2017","journal-title":"Cell Rep."},{"key":"B44","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.neuron.2012.10.032","article-title":"Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma.","volume":"77","author":"Mizutari","year":"2013","journal-title":"Neuron"},{"key":"B45","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/nrd4533","article-title":"New treatment options for hearing loss.","volume":"14","author":"Muller","year":"2015","journal-title":"Nat. Rev. Drug. Discov."},{"key":"B46","doi-asserted-by":"publisher","first-page":"8734","DOI":"10.1523\/jneurosci.0060-16.2016","article-title":"Extensive supporting cell proliferation and mitotic hair cell generation by in vivo genetic reprogramming in the neonatal mouse cochlea.","volume":"36","author":"Ni","year":"","journal-title":"J. Neurosci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"66754","DOI":"10.18632\/oncotarget.11479","article-title":"Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea.","volume":"7","author":"Ni","year":"","journal-title":"Oncotarget"},{"key":"B48","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/978-1-59745-523-7_9","article-title":"Isolation of sphere-forming stem cells from the mouse inner ear.","volume":"493","author":"Oshima","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"7740","DOI":"10.1523\/jneurosci.0554-16.2016","article-title":"The severity of infection determines the localization of damage and extent of sensorineural hearing loss in experimental pneumococcal meningitis.","volume":"36","author":"Perny","year":"2016","journal-title":"J. Neurosci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.heares.2017.04.012","article-title":"Streptococcus pneumoniae-induced ototoxicity in organ of Corti explant cultures.","volume":"350","author":"Perny","year":"2017","journal-title":"Hear. Res."},{"key":"B51","doi-asserted-by":"crossref","first-page":"3160.e3","DOI":"10.1016\/j.celrep.2019.02.053","article-title":"Insights into the biology of hearing and deafness revealed by single-cell RNA sequencing.","volume":"26","author":"Ranum","year":"2019","journal-title":"Cell Rep."},{"key":"B52","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1002\/stem.3315","article-title":"Directed differentiation and direct reprogramming: applying stem cell technologies to hearing research.","volume":"39","author":"Roccio","year":"2020","journal-title":"Stem Cells"},{"key":"B53","doi-asserted-by":"crossref","DOI":"10.1038\/srep17886","article-title":"Cell cycle reactivation of cochlear progenitor cells in neonatal FUCCI mice by a GSK3 small molecule inhibitor.","volume":"5","author":"Roccio","year":"2015","journal-title":"Sci. Rep."},{"key":"B54","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-06334-7","article-title":"Molecular characterization and prospective isolation of human fetal cochlear hair cell progenitors.","volume":"9","author":"Roccio","year":"2018","journal-title":"Nat. Commun."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2019.107859","article-title":"Novel insights into inner ear development and regeneration for targeted hearing loss therapies.","volume":"397","author":"Roccio","year":"2019","journal-title":"Hear. Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1126\/science.3381101","article-title":"Hair cell regeneration after acoustic trauma in adult Coturnix quail.","volume":"240","author":"Ryals","year":"1988","journal-title":"Science"},{"key":"B57","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1016\/j.ymthe.2019.03.017","article-title":"Therapeutic potential of Wnt and notch signaling and epigenetic regulation in mammalian sensory hair cell regeneration.","volume":"27","author":"Samarajeewa","year":"2019","journal-title":"Mol. Ther."},{"key":"B58","doi-asserted-by":"crossref","DOI":"10.1242\/dev.166579","article-title":"Transcriptional response to Wnt activation regulates the regenerative capacity of the mammalian cochlea.","volume":"145","author":"Samarajeewa","year":"2018","journal-title":"Development"},{"key":"B59","doi-asserted-by":"crossref","first-page":"312.e4","DOI":"10.1016\/j.celrep.2019.06.028","article-title":"Atoh1 directs regeneration and functional recovery of the mature mouse vestibular system.","volume":"28","author":"Sayyid","year":"2019","journal-title":"Cell Rep."},{"key":"B60","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis.","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0378-5955(01)00224-6","article-title":"Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals.","volume":"155","author":"Sha","year":"2001","journal-title":"Hear. Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"6470","DOI":"10.1523\/jneurosci.4305-13.2014","article-title":"beta-Catenin is required for hair-cell differentiation in the cochlea.","volume":"34","author":"Shi","year":"2014","journal-title":"J. Neurosci."},{"key":"B63","doi-asserted-by":"publisher","first-page":"9639","DOI":"10.1523\/jneurosci.1064-12.2012","article-title":"Wnt-responsive Lgr5-expressing stem cells are hair cell progenitors in the cochlea.","volume":"32","author":"Shi","year":"2012","journal-title":"J. Neurosci."},{"key":"B64","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-13157-7","article-title":"Renewed proliferation in adult mouse cochlea and regeneration of hair cells.","volume":"10","author":"Shu","year":"2019","journal-title":"Nat. Commun."},{"key":"B65","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.34817","article-title":"Regenerating hair cells in vestibular sensory epithelia from humans.","volume":"7","author":"Taylor","year":"2018","journal-title":"Elife"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-15-66","article-title":"Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss.","volume":"15","author":"Tona","year":"2014","journal-title":"BMC Neurosci."},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000326","article-title":"Uncoordinated maturation of developing and regenerating postnatal mammalian vestibular hair cells.","volume":"17","author":"Wang","year":"2019","journal-title":"PLoS Biol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1126\/science.8456285","article-title":"Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans.","volume":"259","author":"Warchol","year":"1993","journal-title":"Science"},{"key":"B69","doi-asserted-by":"publisher","first-page":"16528","DOI":"10.1074\/jbc.m301372200","article-title":"Targeting presenilin-type aspartic protease signal peptide peptidase with \u03b3-Secretase inhibitors.","volume":"278","author":"Weihofen","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B70","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/cne.903310106","article-title":"Hair cell regeneration after streptomycin toxicity in the avian vestibular epithelium.","volume":"331","author":"Weisleder","year":"1993","journal-title":"J. Comp. Neurol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1016\/s0140-6736(17)31073-5","article-title":"Global hearing health care: new findings and perspectives.","volume":"390","author":"Wilson","year":"2017","journal-title":"Lancet"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1038\/nn1349","article-title":"Math1 regulates development of the sensory epithelium in the mammalian cochlea.","volume":"7","author":"Woods","year":"2004","journal-title":"Nat. Neurosci."},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1101\/739680","article-title":"Development of the mouse and human cochlea at single cell resolution.","author":"Yu","year":"2019","journal-title":"BioRxiv [preprint]"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00186","article-title":"LGR4 and LGR5 regulate hair cell differentiation in the sensory epithelium of the developing mouse cochlea.","volume":"10","author":"Zak","year":"2016","journal-title":"Front. Cell Neurosci."},{"key":"B75","doi-asserted-by":"publisher","first-page":"4551","DOI":"10.1242\/dev.127.21.4551","article-title":"Hes1 is a negative regulator of inner ear hair cell differentiation.","volume":"127","author":"Zheng","year":"2000","journal-title":"Development"},{"key":"B76","doi-asserted-by":"publisher","first-page":"4712","DOI":"10.1523\/jneurosci.21-13-04712.2001","article-title":"Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear.","volume":"21","author":"Zine","year":"2001","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.710159\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T12:33:04Z","timestamp":1725625984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.710159\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,13]]},"references-count":76,"alternative-id":["10.3389\/fcell.2021.710159"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.710159","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,13]]},"article-number":"710159"}}