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RNA-sequence facilitates analyze changes of signaling pathways after drug treatment

ABSTRACT: Mammalian cochlear hair cells cannot regenerate after damage, which was a cause of hearing loss. Due to the small number of cochlear hair cells, we were unable to collect enough cells for research. Therefore, we have established a inner ear organoid model in this way, which greatly expands the number of supporting cells, Lgr5 and gradually mature hair cells. It can be used in high-throughput screening experiments. Using this model for high-throughput screening of FDA small molecule Drug, we found that Regorafenib can promote hair cell regeneration in vitro and get more mature regenerated hair cells. And we found that Regorfenib was though a new VEGF-TGFB axis to regulate hair cell regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE139485 | GEO | 2019/10/29

REPOSITORIES: GEO

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RNA-sequence facilitates analyze changes of signaling pathways after cell reprogramming

Project description:Cochlear hair cells are the sensory cells responsible for transduction of acoustic signals. In mammals, damaged hair cells do not regenerate, resulting in permanent hearing loss. Reprogramming of the surrounding supporting cells to functional hair cells represent a novel strategy to hearing restoration. However, cellular processes governing the efficient and functional hair cell reprogramming are not completely understood. Employing the mouse cochlear organoid system, we performed detailed metabolomic characterizations of the expanding and differentiating organoids. We found that hair cell differentiation is associated with increased mitochondrial electron transport chain (ETC) activity and reactive oxidative species generation. Transcriptome and metabolome analyses indicate reduced expression of oxidoreductases and tricyclic acid (TCA) cycle metabolites. The metabolic decoupling between ETC and TCA cycle limits the availability of the key metabolic cofactors, α-ketoglutarate and NAD+. Reduced expression of NAD+ in cochlear supporting cells by PGC1α deficiency further impairs hair cell reprogramming, while supplementation of α-ketoglutarate and NAD+ promotes hair cell reprogramming both in vitro and in vivo. Our findings reveal metabolic rewiring as a central cellular process during hair cell differentiation, and highlight the insufficiency of key metabolites as a metabolic barrier for efficient hair cell reprogramming.

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