Inner Ear Organoids: Strengths and Limitations

Abstract

Inner ear organoids derived from differentiation of human pluripotent stem cells have recently gained momentum as tools to study inner ear development and developmental defects. An additional exciting aspect about this technology is represented by its translational potential, specifically, the use of organoids to validate therapeutics for hearing and balance restoration on human/patient-specific cells. This latter aspect will be briefly discussed here including opportunities and current limitations.

Keywords: Hearing loss; Human iPSC-derived organoids; Inner ear biology.

Fig. 1

A IEOs contain different otic cell types: sensory epithelia (SE), non-sensory epithelia, neurons, glia, and mesenchyme, but also off-target tissues such as cartilage and epidermis. B Representative example of otic vesicle with sensory epithelium containing MYO7A + hair cells, SOX2 + supporting cells, and TUBB3 + neurons. C Application of IEOs technology: present (blue) and future (pink)

Fig. 2

A Hair cells appear in vivo around W10/12 of development. Hearing onset starts during the third trimester of pregnancy. At birth, the human cochlea is mature with only a few modifications occurring subsequently [41]. Cell degeneration at different time points can result in hearing loss (HL). Early-, late-onset, and age-related hearing loss (ARHL) take place after birth. Congenital HL is caused by early degenerative events occurring still in utero. B The maturity level of IEOs in vitro is currently more suited to assess early defects leading to congenital HL. Potential in vitro artifacts causing culture deterioration need to be carefully evaluated and bypassed to analyze cellular phenotypes. C Representative example of in vitro-derived hair cells at day 60 of differentiation and cochlear hair cells at W12 of development. Adapted from Doda  et al. [14]

Fig. 3

A The comparison between cohorts of iPSC lines (patients and controls) can be used to assess the consequences of the genetic alteration(s). Multiple lines need to be assessed as the different backgrounds are confounding factors. B–C Mutations can be introduced in WT lines or corrected in patient lines to generate isogenic controls. After differentiation in IEOs, phenotypes can be compared within the same genetic background. D Organoids generated from mutant lines can be treated with gene therapy (GT) or with gene/base editors (GE) to assess the efficacy of phenotype reversion. Pink dashed arrows and symbol Δ are used to represent different modalities to compare the generated IEOs

Fig. 4

Summary points discussed in this article including IEO “features” that are already available (green) and that still need to be implemented (blue)