Cell Transplantation to Restore Lost Auditory Nerve Function is a Realistic Clinical Opportunity

Abstract

Hearing is one of our most important means of communication. Disabling hearing loss (DHL) is a long-standing, unmet problem in medicine, and in many elderly people, it leads to social isolation, depression, and even dementia. Traditionally, major efforts to cure DHL have focused on hair cells (HCs). However, the auditory nerve is also important because it transmits electrical signals generated by HCs to the brainstem. Its function is critical for the success of cochlear implants as well as for future therapies for HC regeneration. Over the past two decades, cell transplantation has emerged as a promising therapeutic option for restoring lost auditory nerve function, and two independent studies on animal models show that cell transplantation can lead to functional recovery. In this article, we consider the approaches most likely to achieve success in the clinic. We conclude that the structure and biochemical integrity of the auditory nerve is critical and that it is important to preserve the remaining neural scaffold, and in particular the glial scar, for the functional integration of donor cells. To exploit the natural, autologous cell scaffold and to minimize the deleterious effects of surgery, donor cells can be placed relatively easily on the surface of the nerve endoscopically. In this context, the selection of donor cells is a critical issue. Nevertheless, there is now a very realistic possibility for clinical application of cell transplantation for several different types of hearing loss.

Potential uses of auditory nerve stimulation to modulate immune responses in the inner ear and auditory brainstem

“…Additionally, better mapping of the anatomical and physiological properties of the type II SGN and the innervating efferent fibers could also guide the application of bioelectronic medicine in auditory neuroscience. Finally, combined techniques involving stem cell regenerative therapies augmented with bioelectronic medicine approaches could potentially restore lost AN function (Tang et al, 2018;Guo et al, 2021;Sekiya and Holley, 2021;Fang et al, 2023). Our vision for the future relies on continuous improvements in both basic understanding of the system and new tools to manipulate the nerve function to produce the desired immunological outcomes in the cochlea and auditory system.…”

Is there an unmet medical need for improved hearing restoration?

“…Hair cells are the primary target for regenerative approaches to hearing restoration. Building on pioneering work (summarized in Brigande & Heller, 2009 ), the field has moved forward in devising protocols for generating hair cells, SGNs, or even inner‐ear organoids from stem cells (recent reviews Janesick & Heller, 2019 ; Takeda et al , 2018 ; Wang & Puel, 2018 ; Sekiya & Holley, 2021 ). Koehler et al ( 2017 ) developed a protocol for generating inner‐ear organoids from human‐induced pluripotent stem cells (iPSCs) (Koehler et al , 2017 ).…”

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

“…A common consequence of hair-cell loss is a flat epithelium (Shibata et al, 2010 ), which constitutes a predominated clinical situation of hearing loss that requires a future cure (Yamasoba et al, 2013 ; Yang et al, 2015 ; Homans et al, 2017 ; Revuelta et al, 2017 ; Dawson and Bowl, 2019 ; Dubno, 2019 ; Lopez-Juarez et al, 2019 ). Several studies have focused on various aspects of age-related hearing loss prevention, while others work toward the therapy (Schilder et al, 2019 ; Eshraghi et al, 2020 ; Roccio et al, 2020 ; Sekiya and Holley, 2021 ). For instance, cochlear implants (CI) are effectively used to functionally replace hair cells (Gantz et al, 2018 , 2005 ).…”

“…The presented review will describe mouse mutants to endorse a genetic model with a flat auditory epithelium and associated loss of sensory neurons of the ear and the brainstem. We aim through this approach to inspire innovative research and novel interventions by framing the hallmarks of aging (Campisi, 2013 ; López-Otín et al, 2013 ; Sekiya and Holley, 2021 ) to improve the upcoming translatability of present restoration challenges. Developing those leads to novel mouse models to deal with the strengths and weaknesses.…”