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

Abstract

BackgroundThe 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. This study investigated whether defined humoral cues alone are sufficient to unlock a latent neurogenic program in human Muller cells. MethodsLong-term organotypic retinal cultures were established from 39 adult donors. Cultures were treated with FGF-2 and GSK-3 inhibition to assess proliferation across the peripheral and central retina. Cellular responses were evaluated using single-cell transcriptomics and immunohistochemistry. ResultsFGF-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. ConclusionsThese findings reveal an intrinsic regenerative potential in adult human Muller glia and show that defined humoral cues can activate a latent neurogenic program in these cells. This may have implications for future vision-restoration strategies in degenerative retinal disease.