Identification and characterization of human retinal stem cells capable of retinal regeneration

Abstract Human retinal stem cells hold great promise in regenerative medicine, yet their existence and characteristics remain elusive. Here, we preformed single-cell multi-omics and spatial transcriptomics of human fetal retinas and uncovered a novel cell subpopulation, human neural retinal stem-like cells (hNRSCs), distinct from RPE stem-like cell and traditional retinal progenitor cells. These hNRSCs reside in the peripheral retina within the ciliary marginal zone, exhibiting substantial self-renewal and differentiation potential. We conducted single-cell and spatial transcriptomic analysis of human retinal organoids (hROs), and revealed hROs have remarkable similar hNRSCs consistent with fetal retina, capable of regenerating all retinal cells. Furthermore, we identified crucial transcription factors, notably MECOM, governing hNRSC commitment to neural retinogenesis and regulating hROs regeneration. Transplanting hRO-derived hNRSCs into the rd10 mouse of rapid retinal degeneration significantly repairs the degenerated retina and restores visual function. Together, our work identifies and characterizes a unique category of retinal stem cells from human retinas, underscoring their regenerative potential and promise for transplantation therapy.