Building inner ears: recent advances and future challenges for in vitro organoid systems

Abstract

While inner ear disorders are common, our ability to intervene and recover their sensory function is limited. In vitro models of the inner ear, like the organoid system, could aid in identifying new regenerative drugs and gene therapies. Here, we provide a perspective on the status of in vitro inner ear models and guidance on how to improve their applicability in translational research. We highlight the generation of inner ear cell types from pluripotent stem cells as a particularly promising focus of research. Several exciting recent studies have shown how the developmental signaling cues of embryonic and fetal development can be mimicked to differentiate stem cells into “inner ear organoids” containing otic progenitor cells, hair cells, and neurons. However, current differentiation protocols and our knowledge of embryonic and fetal inner ear development in general, have a bias toward the sensory epithelia of the inner ear. We propose that a more holistic view is needed to better model the inner ear in vitro. Moving forward, attention should be made to the broader diversity of neuroglial and mesenchymal cell types of the inner ear, and how they interact in space or time during development. With improved control of epithelial, neuroglial, and mesenchymal cell fate specification, inner ear organoids would have the ability to truly recapitulate neurosensory function and dysfunction. We conclude by discussing how single-cell atlases of the developing inner ear and technical innovations will be critical tools to advance inner ear organoid platforms for future pre-clinical applications.

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

“…Atoh1 can induce the naïve epithelial cells into hair cells, but the viability of those cells is limited (Jahan et al, 2018 ; Atkinson et al, 2019 ). Beyond neonatal cell conversion (Mantela et al, 2005 ; Kelly et al, 2012 ; Koehler et al, 2017 ; McGovern et al, 2019 ) using pluripotent stem cells (van der Valk et al, 2021 ; Zine et al, 2021 ) to make novel cochlear hair cells that are inner- and outer hair cell-specific is beyond our current ability. Cellular deviations are regularly observed in aged materials and almost all aspects of the cell, including nuclear structure, cellular state, mitochondria, genetic material, and protein function that reduce the outer and inner hair cells with time (Kersigo and Fritzsch, 2015 ; Chessum et al, 2018 ; Wiwatpanit et al, 2018 ; Driver and Kelley, 2020 ; Filova et al, 2020 ; Herranen et al, 2020 ).…”

“…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.…”

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

“…The recent progress in hiPSC derived organoids make it possible to obtain 3D-models of human organ development and study the disease in human relevant cellular and genomic contexts ( 248 – 251 ). Despite some limitations to obtain mature cochlear tissues, current protocols can be used to obtain type I or type II hair cells in 3D-inner ear organoids ( 249 , 251 , 252 ). Further studies are needed to identify key pathways for optimal control of cell differentiation into supporting cells, neurons and/or hair cells according to downstream applications.…”

Regeneration of Hair Cells in the Human Vestibular System

“…Recent studies have succeeded in producing otic organoids from human pluripotent stem cells. Some of them shared many characteristics with human vestibular epithelia ( Koehler et al, 2017 ; Jeong et al, 2018 ; van der Valk et al, 2021 ). In the future, exploring the regulatory mechanisms underlying hair cell formation using organoids and the latest techniques, such as single-cell and single-nuclear sequencing, may help to identify regulatory pathways and key factors which play important roles in the maturation and subtype differentiation of vestibular hair cells.…”