Photobiomodulation as a Potential Regenerative Signal in the Inner Ear: Linking Mitochondrial Redox Signaling to Cell-Fate Regulation.

Photobiomodulation (PBM) is a non-thermal therapeutic modality in which low-intensity red or near-infrared light is used to modulate biological activity. Experimental inner-ear studies report preservation of auditory neurons, attenuation of vestibular injury, improved survival of transplanted stem cells, and changes in otic organoid differentiation. These observations raise the possibility that PBM may influence differentiation-associated cellular states in addition to providing cytoprotection. The classical mechanistic model proposes that photons interact with mitochondrial chromophores, particularly cytochrome c oxidase, leading to changes in respiration, ATP, reactive oxygen species (ROS), nitric oxide, calcium, and downstream signaling; however, a universal primary photoreceptor has not been established. In a 2020 mouse embryonic-stem-cell-derived otic-organoid study, PBM was associated with more organoid-like structures, increased hair-cell-associated markers, increased ROS, and lower Hes5 expression. The RNA-sequencing comparison pooled five embryoid bodies into one sample per condition, limiting biological replication and statistical inference. Accordingly, the Hes5 result should be regarded as exploratory and does not demonstrate direct Notch inhibition. Studies in other regenerative tissues show that PBM can engage ROS-dependent PI3K/AKT/GSK3β/β-catenin signaling, providing a mechanistic precedent rather than proof for the inner ear. This review therefore presents a testable working model in which PBM may connect mitochondrial and redox responses to Wnt/β-catenin and Notch/HES5 pathways during otic differentiation, while emphasizing that mature hair-cell regeneration, new SGN generation, and hearing restoration have not yet been established.