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

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.

Age-Related Hearing Loss: Sensory and Neural Etiology and Their Interdependence

“…Generating vestibular and cochlear hair cells from human pluripotent stem cells have begun the earliest major steps, as mentioned above (Koehler et al, 2017 ; Lahlou et al, 2018 ; Patel et al, 2018 ; Romano et al, 2021 ; van der Valk et al, 2021 ; Zine et al, 2021 ). To date, no one has succeeded in producing both types of the organ of Corti sensory hair cells in vitro in the correct proportion and disparity distribution needed for the restoration of hair cells within the organ of Corti.…”

Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss

“…Moreover, these cells continued their differentiation towards a HC-like lineage following their integration into the sensory epithelia of otic vesicles in chicken embryos; an upregulation in the expression of MYO7A and the hair bundle protein espin (ESPN) was recorded. A series of studies has since attempted the differentiation of pluripotent stem cells (ESCs and iPSCs, of murine and human origins) to otic cell lineages; for detailed reviews on these studies, we refer the reader to some earlier publications [ 20 , 39 , 40 , 41 ]. Within the scope of this review, we address the work that has been carried out using hiPSCs ( Table 1 ), briefly mentioning some results obtained with ESCs.…”

“…A later publication by Jeong and colleagues (2018) reported the emergence in hiPSC-derived inner ear organoids of functionally active vestibular and cochlear HC types; these researchers had applied a series of modifications to the original protocol such as initial culture of the hiPSCs on a layer of mitotically inactivated mouse embryonic fibroblasts, some changes in the number of cells used to generate aggregates, and some medium modifications [ 52 ]. Work is underway to further support the great potential inner ear organoids pose for the field [ 20 , 51 , 66 , 67 ]. They have already been used to model inner ear pathology caused by genetic mutations [ 66 ].…”

“…Many studies are now being conducted on zebrafish, a model that can also undergo genetic modifications and that offers several other advantages, such as a much faster life cycle than that of the mouse and the generation of very large numbers of test organisms that are transparent at their early developmental stages, greatly facilitating their analysis and making the model amenable to high-throughput screenings [ 14 , 15 , 16 ]; nonetheless, the results obtained on this model must be validated on some mammalian system [ 17 , 18 , 19 ]. A critical shortcoming to all these models is that none of them are of human origin and inter-species differences may be expected [ 7 , 20 ]; in this regard, highly relevant data are being obtained from studies on the common marmoset, a non-human primate model of cochlear development and genetic HL [ 21 , 22 , 23 , 24 ]. There are strong indications that the common marmoset may constitute a more predictive model than the mouse since the time course for cochlear development in the former is much longer than in the latter and may thus more closely resemble the human process.…”

Human Brain-Based Models Provide a Powerful Tool for the Advancement of Parkinson’s Disease Research and Therapeutic Development

“…The advent of organoids is considered a major breakthrough in stem cell research and has enabled advancements in the applications of human iPSC for disease modelling. Human heart organoids provide an in vitro model of cardiac development and congenital heart disease ( Lewis-Israeli et al, 2021 ), inner ear organoids have been generated for modelling deafness ( Romano et al, 2021 ), airway epithelial cell organoids are frequently used in lung research ( Eenjes et al, 2021 ), intestinal organoids enable in vitro investigations of gut pathology ( Puschhof et al, 2021 ), and it is even possible to derive sensorimotor organoids capable of forming neuromuscular junctions ( Pereira et al, 2021 ).…”