Stem cell-based strategies for hearing restoration: Current advances and future perspectives

Table 1 Regenerative strategies for major sensorineural hearing loss subtypes

SNHL subtype	Major pathological targets	Potential regenerative strategy	Supporting rationale
Noise-induced cochlear synaptopathy/hidden hearing loss	IHC ribbon synapses, auditory nerve fiber terminals, SGNs	Synapse repair, SGN protection, SGN reinnervation, NT-3 delivery, and CX3CL1/fractalkine-mediated immune modulation, instead of primary hair-cell replacement	Noise exposure can cause loss of IHC-auditory nerve synapses while hair cells may remain present. NT-3 delivery has been shown to regenerate cochlear synapses after acoustic trauma, and resident macrophages as well as CX3CL1/fractalkine signaling can promote ribbon-synapse repair[20,60,122-124]
Genetic hair-cell loss/genetic SNHL with sensory-cell involvement	Depending on the causal gene: Hair cells, supporting cells, synapses, ion channels, motor proteins, or auditory neurons	Gene replacement, gene editing, patient-derived iPSC/organoid modeling, drug screening, and long-term cell replacement when irreversible sensory-cell loss is present	Genetic hearing loss is highly heterogeneous and should be stratified by causal gene and residual cochlear structure. OTOF gene therapy supports gene replacement for selected monogenic synaptopathies, while CRISPR-corrected patient-derived iPSCs with MYO7A or MYO15A mutations support iPSC-based modeling and cell-source development[125-128]
Age-related hearing loss/presbycusis	Hair cells, SGNs, stria vascularis, IHC synapses, mitochondria	Multi-target protection and repair, including antioxidant/anti-inflammatory strategies, EV-based cytoprotection, SGN protection, synapse repair, strial/metabolic support, and selected regenerative approaches	Presbycusis is multifactorial and may involve sensory, neural, strial/metabolic, synaptic, mitochondrial, and inflammatory mechanisms. NT-3 overexpression can prevent age-related IHC synaptopathy and slow hearing decline, supporting synapse-targeted approaches as part of a broader multi-target strategy[129-131]
Auditory neuropathy/neural SNHL	IHC ribbon synapses, presynaptic vesicle release machinery, SGNs, and auditory nerve	Gene therapy for selected synaptopathies such as OTOF-related hearing loss, synapse repair, SGN protection/regeneration, neurotrophic support, auditory neuron replacement, tissue engineering, and cochlear implant-combined strategies	Auditory neuropathy spectrum disorders often involve impaired synaptic transmission or auditory nerve dysfunction rather than primary OHC loss. OTOF-related hearing loss is a prototypical auditory synaptopathy, and SGN protection/regeneration is considered a key therapeutic direction for neural SNHL[126,132,133]
Stria vascularis degeneration/metabolic SNHL	Stria vascularis, cochlear lateral wall, endocochlear potential, K+ recycling, blood-labyrinth barrier	Strial repair, restoration of ion homeostasis, vascular/metabolic support, blood-labyrinth barrier protection, anti-inflammatory/EV-based strategies, and combination approaches rather than sensory-cell replacement alone	The stria vascularis is essential for cochlear fluid homeostasis, K+ recycling, blood-labyrinth barrier function, and generation of the endocochlear potential. Strial dysfunction can independently contribute to SNHL and metabolic presbycusis, so sensory-cell replacement alone may be insufficient[134-137]

SNHL: Sensorineural hearing loss; IHC: Inner hair cell; SGNs: Spiral ganglion neurons; iPSC: Induced pluripotent stem cell; EV: Extracellular vesicle; OHC: Outer hair cell.