Advancements in inner ear development, regeneration, and repair through otic organoids

Abstract

The vertebrate inner ear contains a diversity of unique cell types arranged in a particularly complex 3D cytoarchitecture. Both of these features are integral to the proper development, function, and maintenance of hearing and balance. Since the elucidation of the timing and delivery of signaling molecules to produce inner ear sensory cells, supporting cells, and neurons from human induced pluripotent stem cells, we have entered a revolution using organ-like 'otic organoid' cultures to explore inner ear specific genetic programs, developmental rules, and potential therapeutics. This review aims to highlight a selection of reviews and primary research papers from the past two years of particular merit that use otic organoids to investigate the broadly defined topics of cell reprogramming, regeneration, and repair.

Figure 1:. The wide array of applications of inner ear organoids.

Otic organoids can be used to study basic genetic programs involved in development, where insights in this field have relied heavily on single cell RNA sequencing (scRNAseq) datasets of both animal models in embryonic stages (e.g. mouse) and mature animals that have regenerative potential (e.g. chicken and zebrafish). Inner ear organoids can also recapitulate inner ear dysfunction through genetic mutations (lab-generated hiPSC lines with gene knockout or human mutations or those generated from patient somatic cells), ototoxic drugs, viral infection, or traumatic noise. The high-throughput scalable nature of organoids allows for large drug screens for otoprotective treatments. Otic organoids can be used to further drive breakthroughs on the forefront of regeneration by providing a model to validate targets that induce supporting cell transdifferentiation into hair cells and neurons, and interrogate aging reversal through epigenetic remodeling. Finally, new biological therapeutics that include stem cell replacement, gene therapy, and organ-on-a-chip biomimetic implants will have their basis and testing ground in the field of otic organoid research.