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Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti.

ABSTRACT: Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.

SUBMITTER: Lu X

PROVIDER: S-EPMC9592590 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti.

Lu Xiaoling X Yu Huiqian H Ma Jiaoyao J Wang Kunkun K Guo Luo L Zhang Yanping Y Li Boan B Zhao Zehang Z Li Huawei H Sun Shan S

NPJ Regenerative medicine 20221025 1

Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these ...[more]

PMID: 36280668

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Project description:BackgroundHearing loss is the most common sensory defect afflicting several hundred million people worldwide. In most cases, regardless of the original cause, hearing loss is related to the degeneration and death of hair cells and their associated spiral ganglion neurons. Despite this knowledge, relatively few studies have reported regeneration of the auditory system. Significant gaps remain in our understanding of the molecular mechanisms underpinning auditory function, including the factors required for sensory cell regeneration. Recently, the identification of transcriptional activators and repressors of hair cell fate has been augmented by the discovery of microRNAs (miRNAs) associated with hearing loss. As miRNAs are central players of differentiation and cell fate, identification of miRNAs and their gene targets may reveal new pathways for hair cell regeneration, thereby providing new avenues for the treatment of hearing loss.ResultsIn order to identify new genetic elements enabling regeneration of inner ear sensory hair cells, next-generation miRNA sequencing (miRSeq) was used to identify the most prominent miRNAs expressed in the mouse embryonic inner ear cell line UB/OC-1 during differentiation towards a hair cell like phenotype. Based on these miRSeq results eight most differentially expressed miRNAs were selected for further characterization. In UB/OC-1, miR-210 silencing in vitro resulted in hair cell marker expression, whereas ectopic expression of miR-210 resulted in new hair cell formation in cochlear explants. Using a lineage tracing mouse model, transdifferentiation of supporting epithelial cells was identified as the likely mechanism for this new hair cell formation. Potential miR-210 targets were predicted in silico and validated experimentally using a miR-trap approach.ConclusionMiRSeq followed by ex vivo validation revealed miR-210 as a novel factor driving transdifferentiation of supporting epithelial cells to sensory hair cells suggesting that miR-210 might be a potential new factor for hearing loss therapy. In addition, identification of inner ear pathways regulated by miR-210 identified potential new drug targets for the treatment of hearing loss.

Project description:Following the loss of hair cells from the mammalian cochlea, the sensory epithelium repairs to close the lesions but no new hair cells arise and hearing impairment ensues. For any cell replacement strategy to be successful, the cellular environment of the injured tissue has to be able to nurture new hair cells. This study defines characteristics of the auditory sensory epithelium after hair cell loss.Studies were conducted in C57BL/6 and CBA/Ca mice. Treatment with an aminoglycoside-diuretic combination produced loss of all outer hair cells within 48 hours in both strains. The subsequent progressive tissue re-organisation was examined using immunohistochemistry and electron microscopy. There was no evidence of significant de-differentiation of the specialised columnar supporting cells. Kir4.1 was down regulated but KCC4, GLAST, microtubule bundles, connexin expression patterns and pathways of intercellular communication were retained. The columnar supporting cells became covered with non-specialised cells migrating from the outermost region of the organ of Corti. Eventually non-specialised, flat cells replaced the columnar epithelium. Flat epithelium developed in distributed patches interrupting regions of columnar epithelium formed of differentiated supporting cells. Formation of the flat epithelium was initiated within a few weeks post-treatment in C57BL/6 mice but not for several months in CBA/Ca's, suggesting genetic background influences the rate of re-organisation.The lack of dedifferentiation amongst supporting cells and their replacement by cells from the outer side of the organ of Corti are factors that may need to be considered in any attempt to promote endogenous hair cell regeneration. The variability of the cellular environment along an individual cochlea arising from patch-like generation of flat epithelium, and the possible variability between individuals resulting from genetic influences on the rate at which remodelling occurs may pose challenges to devising the appropriate regenerative therapy for a deaf patient.

Dataset Information

Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti.

Publications

Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti.

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