Multilayered control of retinal stem/progenitor cell fate in the single-cell and organoid era: Developmental blueprints and regenerative opportunities

Irreversible degeneration of retinal neurons and the retinal pigment epithelium is a major cause of vision loss, and current pharmacological or surgical treatments seldom rebuild lost tissue, placing stem cell-based regeneration at the center of therapeutic exploration. Retinal progenitor cells, Müller glia (MG)-derived progenitors, pluripotent stem cell-derived retinal pigment epithelium and photoreceptors, and emerging human retinal stem cell candidates together provide a diverse cellular repertoire whose behavior is governed by tightly coordinated fate-control mechanisms. Enabled by single-cell and spatial multi-omics in developing human retina and retinal organoids, these mechanisms can now be mapped at unprecedented resolution, revealing how distinct lineage trajectories and molecular states arise. This review synthesizes a multilayered framework of fate regulation encompassing the diversity and plasticity of embryonic progenitors, MG-derived progenitors, ciliary margin-like cells and putative adult retinal stem cells, and examines how transcription factor hierarchies, epigenetic landscapes, and non-coding RNAs interact with translational, metabolic and inflammatory cues to shape competence windows and photoreceptor vs inner retinal fates in development and disease. These insights are then connected to next-generation regenerative strategies, including engineered retinal organoids and sheets, MG reprogramming, and rational combinations of gene and cell therapies designed to precisely steer cell identity, maturation and circuit integration. By framing retinal regeneration within this multilayered control paradigm, we highlight key challenges for clinical translation and outline how targeted manipulation of fate-regulatory networks may accelerate the development of safe and effective stem cell therapies for blinding retinal disorders.