Shasha Li

Pigmentation varies widely across humans and is shaped by melanin quantity, type, and spatial distribution. Retinal pigmentation protects against light-induced damage, yet its genetic and evolutionary bases remain unclear. We developed a deep learning framework (DeepGRP) to quantify retinal pigmentation from high-resolution fundus images and conducted a genome-wide association study (GWAS), identifying 42 signals, including 26 previously unidentified loci, with single-nucleotide polymorphism–based heritability of 21.4%. Single-nucleus assay for transposase-accessible chromatin by sequencing and RNA sequencing of human fetal retinal tissues revealed key cellular contributors, including retinal pigment epithelium and photoreceptor cells. Among candidate genes, ARHGAP18 emerged as a previously unrecognized regulator of melanogenesis. Evidence of polygenic adaptation in Europeans suggests selection driven by snow-reflected light at high latitudes. A polygenic risk score for retinal pigmentation correlated with a 4.8-fold higher risk of myopia and a 1.5-fold lower risk of skin cancer. These findings demonstrate the power of deep learning for large-scale ocular phenotyping and reveal insights into the genetic and evolutionary architecture of retinal pigmentation.

Restoring retinal pigment epithelium (RPE) cells is crucial for treating retinal degenerative (RD) diseases, with chemical reprogramming offering a transformative, scalable solution. However, identifying key chemical compounds for generating functional RPE cells from somatic cells remains challenging. Here, we present a two-step chemical reprogramming strategy to convert fibroblasts into functional chemical induced RPE (ciRPE) cells. Leveraging the Single-Cell Reprogramming Compound Finder (scRCF), which integrates transcriptomics-guided predictions with advanced screening, we identified chemical cocktails that precisely reprogram fibroblasts through an intermediate state into ciRPE cells. These ciRPE cells closely mimic the structure and function of native RPE cells, and upon transplantation into RD rats, they seamlessly integrate into host tissue, protect photoreceptors, and restore visual function. Omics and mechanistic analyses revealed that the identified compounds synergistically activate core transcription factors, including Ascl1 and Olig2, orchestrating the reprogramming process. This study provides a scalable, non-integrative approach for generating functional RPE cells, offering a promising strategy for cell replacement therapies targeting RD diseases.

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.

Retinal degeneration (RD) is a leading cause of blindness worldwide and includes conditions such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Stargardt’s disease (STGD). These diseases result in the permanent loss of vision due to the progressive and irreversible degeneration of retinal cells, including photoreceptors (PR) and the retinal pigment epithelium (RPE). The adult human retina has limited abilities to regenerate and repair itself, making it challenging to achieve complete self-replenishment and functional repair of retinal cells. Currently, there is no effective clinical treatment for RD. Stem cell therapy, which involves transplanting exogenous stem cells such as retinal progenitor cells (RPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), or activating endogenous stem cells like Müller Glia (MG) cells, holds great promise for regenerating and repairing retinal cells in the treatment of RD. Several preclinical and clinical studies have shown the potential of stem cell-based therapies for RD. However, the clinical translation of these therapies for the reconstruction of substantial vision still faces significant challenges. This review provides a comprehensive overview of stem/progenitor cell-based therapy strategies for RD, summarizes recent advances in preclinical studies and clinical trials, and highlights the major challenges in using stem/progenitor cell-based therapies for RD. Graphical Abstract