A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss

Abstract

The sense of hearing depends on a specialized sensory organ in the inner ear, called the cochlea, which contains the auditory hair cells (HCs). Noise trauma, infections, genetic factors, side effects of ototoxic drugs (ie, some antibiotics and chemotherapeutics), or simply aging lead to the loss of HCs and their associated primary neurons. This results in irreversible sensorineural hearing loss (SNHL) as in mammals, including humans; the inner ear lacks the capacity to regenerate HCs and spiral ganglion neurons. SNHL is a major global health problem affecting millions of people worldwide and provides a growing concern in the aging population. To date, treatment options are limited to hearing aids and cochlear implants. A major bottleneck for development of new therapies for SNHL is associated to the lack of human otic cell bioassays. Human induced pluripotent stem cells (hiPSCs) can be induced in two-dimensional and three-dimensional otic cells in vitro models that can generate inner ear progenitors and sensory HCs and could be a promising preclinical platform from which to work toward restoring SNHL. We review the potential applications of hiPSCs in the various biological approaches, including disease modeling, bioengineering, drug testing, and autologous stem cell based-cell therapy, that offer opportunities to understand the pathogenic mechanisms of SNHL and identify novel therapeutic strategies.

ISL1 is necessary for auditory neuron development and contributes towards tonotopic organization

“…Altogether, our study provides compelling evidence that ISL1 is a critical regulator of SGN development, affecting neuronal migration, pathfinding abilities to form cochlear wiring, and central axonal projections. As such, ISL1 represents an essential factor in the regulation of neuronal differentiation to produce functional neurons in cell-based therapies and stem cell engineering 96, 97 . Additionally, this unique model contributes to our understanding of how disorganization of the neuronal periphery affects information processing at higher centers of the central auditory pathway at the physiological and behavioral levels.…”

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.…”

“…The model appears to have limited transformation of supporting cells into HCs (Walters et al, 2017 ; Yamashita et al, 2018 ; Roccio et al, 2020 ; Li et al, 2020 ). In contrast, age-related hearing loss is understudied compared to earliest hair cell replacements (Zine et al, 2014 , 2021 ; Devare et al, 2018 ; Yamoah et al, 2020 ). Notably, we realize that the stages of mouse development are different compared to humans (Lim and Brichta, 2016 ; Wang et al, 2018 ): a 2-year-old mouse is equivalent to a ~70-year-old human ( Figure 1A ).…”

Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

“…To this aim, stem cell-based inner ear cell cultures derived from human embryonic stem cells as well as human-induced pluripotent stem cells provide a promising tool in the future. Stem cell-based inner ear cell cultures will be scalable and will allow generating transplantable sensory and neural progenitors in vitro , to replace the lost cell type in vivo ( Chen et al, 2012 ; Koehler et al, 2017 ; Zine et al, 2021 ). In general, stem cell-based cell cultures use externally applied growth factors and small molecules to recapitulate the differentiation programs employed during development.…”