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

Figure 1 Retinal regenerative lineage library: Sources vs controllability/scalability/translational fit. A: Lineage/cell source library: A categorization of the major regenerative substrates discussed in this review. Embryonic retinal progenitor cells (RPCs) serve primarily as developmental blueprints (reference only). Among adult-associated substrates, Müller glia (MG)-based approaches and human pluripotent stem cell-derived products represent the most tractable therapeutic routes, whereas ciliary marginal zone-like/adult-candidate populations are presented here as hypothesis-generating developmental-edge programs with currently limited evidence as a near-term clinical cell source; B: Decision matrix & indication stage: A multi-axis evaluation of these sources based on three translational criteria: Controllability: The precision of fate specification and stability of the maturation state [high in RPCs/retinal pigment epithelium (RPE); lower in MG/ciliary marginal zone]. Scalability: Good Manufacturing Practice manufacturing readiness (highest in human pluripotent stem cell-derived RPE). Integration burden: The complexity of host connectivity required for function (highest for photoreceptors/RPCs; lowest for RPE). The bottom timeline maps these sources to their “best-fit” disease stages, proposing MG reprogramming for early-stage intervention and cell replacement (RPE/photoreceptors) for intermediate-to-end-stage degeneration. Critical cautions: Key risks are highlighted, including adeno-associated virus promoter leakage artifacts in MG studies, the confounding of material transfer vs synaptic integration in photoreceptor grafts, and surgical complexity for RPE patches. RPCs: Retinal progenitor cells; Nuclear factor I; Prox1: Prospero homeobox 1; AAV: Adeno-associated virus; CMZ: Ciliary marginal zone; hPSC: Human pluripotent stem cell; RPE: Retinal pigment epithelium; GMP: Good Manufacturing Practice; PVR: Proliferative vitreoretinopathy; QC: Quality control.