Regulation of Spiral Ganglion Neuron Regeneration as a Therapeutic Strategy in Sensorineural Hearing Loss

Abstract

In the mammalian cochlea, spiral ganglion neurons (SGNs) are the primary neurons on the auditory conduction pathway that relay sound signals from the inner ear to the brainstem. However, because the SGNs lack the regeneration ability, degeneration and loss of SGNs cause irreversible sensorineural hearing loss (SNHL). Besides, the effectiveness of cochlear implant therapy, which is the major treatment of SNHL currently, relies on healthy and adequate numbers of intact SGNs. Therefore, it is of great clinical significance to explore how to regenerate the SGNs. In recent years, a number of researches have been performed to improve the SGNs regeneration strategy, and some of them have shown promising results, including the progress of SGN regeneration from exogenous stem cells transplantation and endogenous glial cells’ reprogramming. Yet, there are challenges faced in the effectiveness of SGNs regeneration, the maturation and function of newly generated neurons as well as auditory function recovery. In this review, we describe recent advances in researches in SGNs regeneration. In the coming years, regenerating SGNs in the cochleae should become one of the leading biological strategies to recover hearing loss.

WNT Activation and TGFβ-Smad Inhibition Potentiate Stemness of Mammalian Auditory Neuroprogenitors for High-Throughput Generation of Functional Auditory Neurons In Vitro

“…Auditory neurons are particularly relevant targets in the context of cochlear implantation, which remains, thus far, the only available solution for deaf patients. Therefore, spiral ganglion regeneration has recently gained increased attention as a therapeutic strategy in this context [ 34 ]. To date, stem cell transplantation [ 35 , 36 ] and neuronal conversion from glial cells [ 37 , 38 , 39 ] are the two main strategies employed for SGN regeneration.…”

A basement membrane extract-based three-dimensional culture system promotes the neuronal differentiation of cochlear Sox10-positive glial cells in vitro

“…Spiral ganglion neurons (SGNs) in the mammalian inner ear are the first neural element in the auditory conduction pathway, as they acquire and deliver acoustic information from cochlear hair cells (HCs) to the central nervous system, thereby allowing the establishment of auditory cognition [ 1 ]. As terminally differentiated cells, SGNs cannot regenerate by themselves, and thus any damage to them due to genetic or environmental factors leads to irreversible sensorineural hearing loss (SNHL) [ 2 ]. However, currently, there is no effective treatment to biologically replace damaged SGNs.…”

“…In the postnatal cochlea, GCs are involved in promoting the development and survival of SGNs by providing neuregulin and neurotrophic support [ [10] , [11] , [12] ], as well as maintaining the proper function of SGN [ 13 ]. Recently, studies have identified the neonatal inner ear GCs as a potential source of neural stem/progenitor cells (NSPs) for SGN regeneration [ 2 ]. For example, the quiescent GCs could be activated and initiate proliferation after SGN degeneration [ 7 , 14 ], several subtypes of GCs, such as proteolipid protein (PLP1)-positive GCs [ 4 ], Sox2-positive glial population [ 15 ], can give rise to neurons and GCs, but not HCs, in vitro or in vivo .…”

“…For example, the quiescent GCs could be activated and initiate proliferation after SGN degeneration [ 7 , 14 ], several subtypes of GCs, such as proteolipid protein (PLP1)-positive GCs [ 4 ], Sox2-positive glial population [ 15 ], can give rise to neurons and GCs, but not HCs, in vitro or in vivo . SGN regeneration from in situ cochlear GCs has many advantages [ 2 ] such as technical ease of implementation without the need for exogenous cell transplantation and a reduced risk of tumor formation [ 16 ]. However, the numbers of these reported GCs as well as their neuronal differentiation capacity are quite limited, therefore, strategies to promote the proliferation, neuronal differentiation, and survival of inner ear NSPs will be conducive to developing strategies for SGN regeneration and hearing restoration.…”

Wnt signaling enhances the capacity of cochlear Frizzled 10-positive glial cells as neural stem cells

“…Recent studies have uncovered some promising results in SGNs regeneration, including the differentiation of exogenous stem cells into SGNs and the reprogramming of endogenous glial cells (GCs) in the inner ear 10 . GCs in the inner ear include Schwann cells, which exist along the neuronal bers, and satellite cells, which surround and myelinate ganglionic neuronal cell bodies 11 .…”