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Degeneration or loss of inner ear hair cells (HCs) is irreversible and results in sensorineural hearing loss (SHL). Human-induced pluripotent stem cells (hiPSCs) have been employed in disease modelling and cell therapy. Here, we propose a transcription factor (TF)-driven approach using  ATOH1  and regulatory factor of x-box ( RFX ) genes to generate HC-like cells from hiPSCs. Our results suggest that  ATOH1 / RFX1/RFX3  could significantly increase the differentiation capacity of iPSCs into  MYO7A  mCherry -positive cells, upregulate the mRNA expression levels of HC-related genes and promote the differentiation of HCs with more mature stereociliary bundles. To model the molecular and stereociliary structural changes involved in HC dysfunction in SHL, we further used  ATOH1/RFX1/RFX3  to differentiate HC-like cells from the iPSCs from patients with myoclonus epilepsy associated with ragged-red fibres (MERRF) syndrome, which is caused by A8344G mutation of mitochondrial DNA (mtDNA), and characterised by myoclonus epilepsy, ataxia and SHL. Compared with isogenic iPSCs, MERRF-iPSCs possessed ~42–44% mtDNA with A8344G mutation and exhibited significantly elevated reactive oxygen species (ROS) production and  CAT  gene expression. Furthermore, MERRF-iPSC-differentiated HC-like cells exhibited significantly elevated ROS levels and  MnSOD  and  CAT  gene expression. These MERRF-HCs that had more single cilia with a shorter length could be observed only by using a non-TF method, but those with fewer stereociliary bundle-like protrusions than isogenic iPSCs-differentiated-HC-like cells could be further observed using  ATOH1/RFX1/RFX3  TFs. We further analysed and compared the whole transcriptome of M1 ctrl -HCs and M1-HCs after treatment with  ATOH1  or  ATOH1/RFX1/RFX3 . We revealed that the HC-related gene transcripts in M1 ctrl -iPSCs had a significantly higher tendency to be activated by  ATOH1/RFX1/RFX3  than M1-iPSCs. The  ATOH1/RFX1/RFX3  TF-driven approach for the differentiation of HC-like cells from iPSCs is an efficient and promising strategy for the disease modelling of SHL and can be employed in future therapeutic strategies to treat SHL patients.

cell death and disease

ATOH1/RFX1/RFX3 transcription factors facilitate the differentiation and characterisation of inner ear hair cell-like cells from patient-specific induced pluripotent stem cells harbouring A8344G mutation of mitochondrial DNA