High-throughput screening on cochlear organoids identifies VEGFR-MEK-TGFB1 signaling promoting hair cell reprogramming.
Stem Cell Reports
; 16(9): 2257-2273, 2021 09 14.
Article
em En
| MEDLINE
| ID: mdl-34525385
ABSTRACT
Hair cell degeneration is a major cause of sensorineural hearing loss. Hair cells in mammalian cochlea do not spontaneously regenerate, posing a great challenge for restoration of hearing. Here, we establish a robust, high-throughput cochlear organoid platform that facilitates 3D expansion of cochlear progenitor cells and differentiation of hair cells in a temporally regulated manner. High-throughput screening of the FDA-approved drug library identified regorafenib, a VEGFR inhibitor, as a potent small molecule for hair cell differentiation. Regorafenib also promotes reprogramming and maturation of hair cells in both normal and neomycin-damaged cochlear explants. Mechanistically, inhibition of VEGFR suppresses TGFB1 expression via the MEK pathway and TGFB1 downregulation directly mediates the effect of regorafenib on hair cell reprogramming. Our study not only demonstrates the power of a cochlear organoid platform in high-throughput analyses of hair cell physiology but also highlights VEGFR-MEK-TGFB1 signaling crosstalk as a potential target for hair cell regeneration and hearing restoration.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Organoides
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Cóclea
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Quinases de Proteína Quinase Ativadas por Mitógeno
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Receptores de Fatores de Crescimento do Endotélio Vascular
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Fator de Crescimento Transformador beta1
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Reprogramação Celular
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Ensaios de Triagem em Larga Escala
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
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Screening_studies
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China