Proliferative Capacity and Neural Lineage Commitment of Muller Glia in the Adult Human Retina

The mammalian retina lacks meaningful regenerative capacity, and degeneration usually leads to irreversible vision loss. Although lower vertebrates regenerate retinal neurons through Muller glia, this capacity has generally been considered absent in humans. Using long-term organotypic retinal cultures from 39 adult donors, we show that defined humoral cues alone are sufficient to unlock a latent neurogenic program in human Muller cells. FGF-2 treatment and GSK-3 inhibition induced robust proliferation across both peripheral and central retina, with 79.09 {+/-} 6.32% of dividing cells identified as Muller glia, some completing multiple cell cycles. Single-cell transcriptomics revealed activation of progenitor-like and neuronal differentiation pathways, whereas immunohistochemistry demonstrated expression of early and late neuronal markers spanning all major retinal lineages. Newly generated cells expressed markers of cone, rod, bipolar, horizontal, amacrine, and ganglion cell identities, together with evidence of early synaptogenesis. These findings reveal an intrinsic regenerative potential in adult human Muller glia, with implications for future vision-restoration strategies in degenerative retinal disease. SummaryAdult human Muller glia retain an intrinsic capacity for proliferation and neural lineage commitment independent of donor age or gender. In long-term organotypic cultures of human donor retina, defined humoral cues, without genetic manipulation, induce Muller glia proliferation and the onset of neuronal differentiation. These findings reveal intrinsic neurogenic potential in human Muller glia and provide a human-relevant platform for retinal regeneration studies.