NAMPT activity plays a key role in driving autoimmune processes that mediate beta-cell death and type 1 diabetes development in mice.

The human retina is a complex neural tissue that captures light and initiates visual processing through the action of photoreceptor cells - rods and cones - whose development requires precise orchestration of gene expression, polarity, morphogenesis, and synaptogenesis. Retinal organoids derived from human pluripotent stem cells have emerged as powerful models to study these processes in vitro; however, they typically exhibit incomplete structural and functional maturation features. These limitations are especially pronounced in long-term cultures and remain a bottleneck for both fundamental and translational applications. Additionally, they have far-reaching consequences. In disease modelling, immature photoreceptors may fail to replicate key pathological features of inherited retinal disorders, limiting the utility of organoids for studying disease progression or testing therapeutic interventions. In drug discovery, insufficient maturation hampers the ability to assess compound efficacy on functional phototransduction or synaptic signalling. Critically, in the context of photoreceptor transplantation, a promising strategy for restoring vision in degenerative retinal diseases, the ability of donor cells to survive, integrate, and contribute to visual function largely depends on the maturity of cells and synaptic machinery. Therefore, strategies that promote the maturation of photoreceptors in retinal organoids are urgently needed to improve the fidelity, functionality, and clinical relevance of this model system. While advances in organoid engineering have shown that physical and sensory cues, such as mechanical strain, electrical stimulation, or circadian entrainment, can promote the maturation of other stem cell-derived tissues (e.g., cardiomyocytes, neurons, β-cells), the role of light as a developmental stimulus on the retina has been largely overlooked. This is surprising given that light is not only the physiological target of photoreceptors but also an essential instructive signal during retinal development in vivo. Here, we address this fundamental and previously untested question: Can light, delivered in a controlled, rhythmic pattern, promote the maturation of human photoreceptors and strengthen synaptic connectivity? By applying 40 Hz flickering light in a 12-h light/12-h dark cycle, we demonstrate that photostimulation markedly enhances photoreceptor maturation at structural, transcriptomic, and synaptic levels while strengthening electrophysiological responses downstream of photoreceptors. In doing so, we identify light not only as a sensory end-point but as a developmental signal for guiding human retinal differentiation.