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

Figure 1 Cochlear functional unit and therapeutic targets for hearing restoration. The upper panel illustrates the cross-sectional anatomy of the organ of Corti, highlighting that hearing restoration requires the integrated reconstruction of a multicellular unit rather than a single cell type. Key targets include hair cells (mechanoelectrical transduction), supporting cells (structural support and regenerative competence), spiral ganglion neurons (auditory signal relay), ribbon synapses (sensory-neural connectivity), and the stria vascularis/Lateral wall (ionic homeostasis and metabolic support). The lower panel summarizes three major stem cell-based therapeutic paradigms: Exogenous cell replacement utilizing pluripotent stem cells (module 1); endogenous progenitor activation and supporting-cell reprogramming (module 2); and cell-free repair mediated by stem cell-derived extracellular vesicles for niche modulation (module 3). IHC: Inner hair cell; OHC: Outer hair cell; PSCs: Pluripotent stem cells; SGN: Spiral ganglion neuron; EV: Extracellular vesicle.

Figure 2 Stem cell-based strategies for cochlear repair and hearing restoration. This schematic summarizes major regenerative approaches for sensorineural hearing loss. Cochlear injury involves hair-cell loss, spiral ganglion neuron damage, synaptic disruption, and microenvironmental dysfunction. Pluripotent stem cells, mesenchymal stem/stromal cells, stem cell-derived extracellular vesicles, endogenous progenitor/supporting cells, and cochlear organoids provide complementary strategies for cell replacement, trophic support, cell-free protection, in situ reprogramming, and preclinical modeling. These approaches converge on hair-cell repair, spiral ganglion neuron protection, synaptic support, microenvironmental modulation, and ultimately hearing restoration. IHC: Inner hair cell; OHC: Outer hair cell; SGN: Spiral ganglion neuron; ESCs: Embryonic stem cells; iPSCs: Induced pluripotent stem cells; MSCs: Mesenchymal stem/stromal cells; BDNF: Brain-derived neurotrophic factor; GDNF: Glial cell line-derived neurotrophic factor; IGF-1: Insulin-like growth factor 1; VEGF: Vascular endothelial growth factor; miRNA: MicroRNA.

Figure 3 Evolution of stem cell-related strategies for hearing restoration from 1990 to 2025. The timeline summarizes the emergence and major progress of key strategies, including pluripotent stem cell-derived auditory cells, endogenous reprogramming, mesenchymal stem/stromal cell/extracellular vesicle-based therapies, cochlear organoids, spiral ganglion neuron/circuit repair, and bioengineering-assisted cochlear implant integration. PSC: Pluripotent stem cell; MSC: Mesenchymal stem/stromal cell; EV: Extracellular vesicle; SGN: Spiral ganglion neuron; hESC: Human embryonic stem cell; hPSC: Human pluripotent stem cell.