MiR-210 promotes sensory hair cell formation in the organ of corti.
BACKGROUND
Hearing 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.


RESULTS
In 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.


CONCLUSIONS
MiRSeq 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.
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Sabrina
S
Riccardi
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Sebastian
S
Bergling
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Cambridge, USA.
Frederic
F
Sigoillot
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Martin
M
Beibel
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Annick
A
Werner
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Juliet
J
Leighton-Davies
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Judith
J
Knehr
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Tewis
T
Bouwmeester
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Christian N
CN
Parker
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
Guglielmo
G
Roma
Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland. bernd.kinzel@novartis.com.
Bernd
B
Kinzel
D000818:Animals; D002460:Cell Line; D054338:Cell Transdifferentiation; D055879:Gene Knock-In Techniques; D006199:Hair Cells, Auditory, Inner / Q000166:cytology*; D059014:High-Throughput Nucleotide Sequencing; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000166:cytology*; D012038:Regeneration; D055748:SOXB1 Transcription Factors / Q000235:genetics; D017423:Sequence Analysis, RNA
C549325:MIRN210 microRNA, mouse; D035683:MicroRNAs; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse
Hearing loss; MiR-210; Next generation sequencing; Transdifferentiation