Today's open access paper is a review of present progress towards regenerative therapies that can reverse hearing loss. Progressive hearing loss is pervasive in old age, and accelerates considerable in the later stages of life. Hearing loss correlates with cognitive decline, and while it is plausible that this is because of degeneration of central nervous system function, there is also the consideration that loss of hearing isolates people and deprives them of interactions that stimulate brain activity. It is well demonstrated in mice that environment richness has a strong impact on the brain and its pace of aging.
Much of the research into age-related hearing loss is focused on the sensory hair cells of the inner ear. These detect the pressure waves of sound and in response pass impulses into nervous system connections leading to the brain. There is some evidence for loss of these cells to be the problem, and some evidence for the cells to survive in sufficient numbers, but lose their connections to the brain. Numerous research teams over the past decade or more have worked on producing regenerative therapies to regrow functional hair cells in the aged inner ear. Numerous strategies have been attempted, such as adapting mechanisms from regenerative species that can regrow hair cells as adults, or direct stimulation of pathways such as Notch that are associated with growth. Varying degrees of success have been demonstrated in mice, but as is often the case, progress towards the clinic remains frustratingly slow.
More than 5% of the world population lives with some degree of hearing impairment. The main factors behind hearing degeneration are ototoxic drugs, aging, continued exposure to excessive noise and infections. After an injury, the auditory system is damaged irreversibly, because the regeneration system is inhibited or deactivated in higher mammals, oppositely to other non-mammalian vertebrates. The pool of adult stem cells in the inner ear drops dramatically after birth. Therefore, an endogenous cellular source for regeneration is absent. In mammals, hair cells (HCs) are only generated during a short embryonic period; hence, their loss in adults produces an irreversible hearing defect. Similarly, the spiral ganglion neurons (SGNs) degeneration is unrecoverable and in the case of synaptic loss, recovery has been shown to be limited.
Because of the drastic reduction in the number of stem cells in the inner ear after the neonatal period, the autonomous regenerating capacity is almost depleted. Therefore, many research groups have focused their efforts on developing stem cell-based treatments to restore HC, SGN, and SC populations. The auditory regeneration field is mainly focus on embryonic stem cells, adult stem cells, or induced pluripotent stem cells (iPSCs). However, nowadays the main issues to be solved are the obtaining of a proper efficiency in the production of auditory stem cells and to demonstrate the utility and safety of these cells in a clinical context. Experimentation in animal models with regenerative capacity, such as zebrafish or avian models, has shown that their auditory regeneration is guided by the same genetic pathways activated during embryonic development. That mechanism leads to HC or stereocilia regeneration by different mechanisms, that have aroused great interest for the development of novel therapies that can reconstruct these pathways in humans.
In our opinion, the important discoveries in this area are mainly focused on the development of methods for stem cell transplantation, improving migration, survival, and new genetic systems for cell fate monitoring. Different routes for stem cell transplantation to the cochlea have been tested, such as through the perilymph or the endolymph. Although these techniques are promising, their results show a low cell survival rate, with only small populations of new cells at the target tissue. Transplantation of cells into the modiolus (bone lamina inside the cochlea) or in the cochlear nerve, showed a higher cell survival rate and increased migration to the target. However, the transplantation process involves potential hearing damage. The direct transplantation of stem cells on the side wall tissue of the cochlea seems to achieve efficient results. The abundance of tissue and blood supply to the area, may be responsible for the increased survival of grafted cells in the wall.
In our opinion, hearing regeneration should be considered from a multidisciplinary point of view, not only focused on stem cells, but also considering molecular mediators as a strategy to improve the outcome. Some combined therapies have been shown to be a better approach to treat some diseases than singular therapies, for instance, stem cell delivery with gene therapy to treat critical limb ischemia. The transplantation of stem cell-derived otic progenitors or adult stem cells (as neural stem cells), results in a significant improvement in hearing, which is especially noticeable in neuronal regeneration. However, the cells have to properly migrate to the damaged area and promote the establishment of functional synaptic connections between HCs and SGNs, which could be improved with molecular mediators or genetic engineering.