Riccardi, Sabrina, Bergling, Sebastian, Sigoillot, Frederic, Beibel, Martin, Werner, Annick, Leighton-Davies, Juliet, Knehr, Judith, Bouwmeester, Antonius, Parker, Christian, Roma, Guglielmo and Kinzel, Bernd (2016) Mir-210 promotes sensory hair cell formation in the organ of Corti. BMC Genomics, 17 (309). pp. 1-14. ISSN 1471-2164

Abstract

Background:
Hearing loss is the most common sensory defect with several hundred million people worldwide having hearing disorders. In most cases, the cause of hearing loss is related to the degeneration and death of hair cells and their associated spiral ganglion neurons. However, 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 and thereby provide new avenues for the treatment of hearing loss.
Results:
In order to identify new genetic elements enabling regeneration of sensory hair cells in the inner ear, next-generation miRNA sequencing (miRSeq) was used to identify the most prominent microRNAs expressed in the mouse embryonic inner ear cell line UB/OC-1 during differentiation towards a hair cell like phenotype. Based on miRSeq we selected eight most differentially expressed miRNAs for further characterization. Of those, miR-210 knock-down in vitro resulted in hair cell marker expression in UB-OC1, whereas ectopic expression of miR-210 resulted in new hair cell formation in cochlear explants. By using a lineage tracing mouse model, we identified transdifferentiation of supporting epithelial cells as the likely mechanism for new hair cell formation. Potential miR-210 targets were predicted in silico and identified experimentally using a miR-trap approach.
Conclusion:
MiRSeq followed by ex vivo validation revealed miR-210 as a novel factor driving transdifferentiation of supporting epithelial cells to sensory hair cells. Our data suggest that miR-210 might be a potential new factor for hearing loss therapy. Moreover, identification of inner ear pathways regulated by miR-210 identified novel drug targets for the treatment of hearing loss.

Item Type:	Article
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/24572