Deafness-in-a-dish: modeling hereditary deafness with inner ear organoids

Daniel R Romano,Rick F Nelson,Eri Hashino

doi:10.1007/s00439-021-02325-9

Daniel R Romano, Rick F Nelson + Show 1 more

Open Access

https://doi.org/10.1007/s00439-021-02325-9

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Abstract

Sensorineural hearing loss (SNHL) is a major cause of functional disability in both the developed and developing world. While hearing aids and cochlear implants provide significant benefit to many with SNHL, neither targets the cellular and molecular dysfunction that ultimately underlies SNHL. The successful development of more targeted approaches, such as growth factor, stem cell, and gene therapies, will require a yet deeper understanding of the underlying molecular mechanisms of human hearing and deafness. Unfortunately, the human inner ear cannot be biopsied without causing significant, irreversible damage to the hearing or balance organ. Thus, much of our current understanding of the cellular and molecular biology of human deafness, and of the human auditory system more broadly, has been inferred from observational and experimental studies in animal models, each of which has its own advantages and limitations. In 2013, researchers described a protocol for the generation of inner ear organoids from pluripotent stem cells (PSCs), which could serve as scalable, high-fidelity alternatives to animal models. Here, we discuss the advantages and limitations of conventional models of the human auditory system, describe the generation and characteristics of PSC-derived inner ear organoids, and discuss several strategies and recent attempts to model hereditary deafness in vitro. Finally, we suggest and discuss several focus areas for the further, intensive characterization of inner ear organoids and discuss the translational applications of these novel models of the human inner ear.

Highlights

An estimated 430 million people worldwide (13 million in the United States) have moderate-to-profound hearing loss (GBD Hearing Loss Collaborators 2021; Goman and Lin 2016)
Another limitation of induced PSCs (iPSCs) is the rarity of specific single-gene mutations, which are often only reported in individual families
Since the human inner ear cannot be biopsied without causing significant, irreversible damage to the hearing or balance organ, the biological study of human inner ear cells has traditionally been limited to scarce fetal and cadaveric tissues

Summary

Introduction

An estimated 430 million people worldwide (13 million in the United States) have moderate-to-profound hearing loss (GBD Hearing Loss Collaborators 2021; Goman and Lin 2016). While more than 99% of genes in the mouse genome have a human homologue (with approximately 80% having a one-to-one orthologue) (Mouse Genome Sequencing Consortium 2002), the targeted introduction of human deafness-related mutations into the mouse genome does—in some cases—fail to produce a deafness phenotype (Lu et al 2014; Tona et al 2020), suggesting that the sequence homology of a gene does not necessarily translate to functional identicality of its end-product This was demonstrated more systematically by Liao and Zhang (2008), who found that more than 20% of a sample of one-to-one mouse orthologues of human essential genes (i.e., those genes required for survival to reproductive age or reproduction itself) were non-essential

In vitro generation of inner ear tissue

Unsettled questions in inner ear organoid research

Clinical findings

Translational applications of inner ear organoids

Findings

Summary