High-throughput screening on cochlear organoids identifies VEGFR-MEK-TGFB1 signaling promoting hair cell reprogramming.
Animals
Cell Culture Techniques, Three Dimensional
/ methods
Cell Differentiation
/ drug effects
Cells, Cultured
Cellular Reprogramming
/ genetics
Cochlea
/ cytology
Drug Discovery
/ methods
Drug Evaluation, Preclinical
Gene Expression Regulation
/ drug effects
Hair Cells, Auditory
/ cytology
High-Throughput Screening Assays
Mice
Mice, Transgenic
Mitogen-Activated Protein Kinase Kinases
/ metabolism
Organoids
/ cytology
Phenylurea Compounds
/ pharmacology
Pyridines
/ pharmacology
Receptors, G-Protein-Coupled
/ genetics
Receptors, Vascular Endothelial Growth Factor
/ metabolism
Signal Transduction
/ drug effects
Transforming Growth Factor beta1
/ metabolism
Regorafenib
drug screening
hair cells
inner ear
organoids
reprogramming
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
11
06
2021
revised:
17
08
2021
accepted:
17
08
2021
entrez:
15
9
2021
pubmed:
16
9
2021
medline:
11
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34525385
pii: S2213-6711(21)00428-8
doi: 10.1016/j.stemcr.2021.08.010
pmc: PMC8452601
pii:
doi:
Substances chimiques
Lgr5 protein, mouse
0
Phenylurea Compounds
0
Pyridines
0
Receptors, G-Protein-Coupled
0
Transforming Growth Factor beta1
0
regorafenib
24T2A1DOYB
Receptors, Vascular Endothelial Growth Factor
EC 2.7.10.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2257-2273Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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