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

Human retinal stem cells hold great promise in regenerative medicine, yet their existence and characteristics remain elusive. Here, we performed single-cell multiomics and spatial transcriptomics of human fetal retinas and uncovered a cell subpopulation, human neural retinal stem-like cells (hNRSCs), distinct from retinal pigment epithelium stem-like cells and traditional retinal progenitor cells. We found that these hNRSCs reside in the peripheral retina in the ciliary marginal zone, exhibiting substantial self-renewal and differentiation potential. We conducted single-cell and spatial transcriptomic analyses of human retinal organoids (hROs) and revealed that hROs contain a population of hNRSCs with similar transcriptional profiles and developmental trajectories to hNRSCs in the fetal retina potentially capable of regenerating all retinal cells. Furthermore, we identified crucial transcription factors, such as MECOM, governing hNRSC commitment to neural retinogenesis and regulating repair processes in hROs. hRO-derived hNRSCs transplanted into the rd10 mouse model of retinitis pigmentosa differentiated and were integrated into the retina, alleviated retinal degeneration, and improved visual function. Overall, our work identifies and characterizes a distinct category of retinal stem cells from human retinas, underscoring their regenerative potential and promise for transplantation therapy.