SULT1A4 is associated with a subpopulation of human iPSC–derived retinal progenitor cells with pronounced migration and regenerative efficacy in RD models

Retinal degenerative (RD) diseases currently lack effective treatments capable of reversing photoreceptor loss, which poses a major challenge to visual regenerative medicine. Although retinal cells derived from induced pluripotent stem cells (iPSCs) have therapeutic potential, their clinical application is limited by low differentiation efficiency and poor post-transplantation survival. Herein, we established a stable and expandable protocol for efficient differentiation of human iPSCs into retinal progenitor cells (RPCs) within 3 weeks under chemically defined medium (CDM) conditions. Through single cell cloning, we isolated a functionally enhanced subgroup, designated human retinal progenitor cell 1 (hRPC1), which exhibited increased mitochondrial activity and sulfotransferase 1A4 ( SULT1A4) associated dopamine (DA) metabolism thus confers resistance to oxidative stress and stabilizes mitochondrial function. Following transplantation into RD models, hRPC1 cells showed notable integration into the host retina, along with substantial structural preservation and functional recovery within 4–8 weeks. The obvious in vivo performance of hRPC1 was accompanied by distinct metabolic features, while functional studies identified SULT1A4 as a candidate associated with cellular energetic and redox homeostasis. Together, these mechanisms support the restoration of visual function in RD models. Our findings provide a novel strategy for identifying highly active, transplantable hRPCs to improve the therapeutic efficacy of cell transplantation. In this study, in vivo a repeatable, expandable, and chemically defined differentiation platform with a clearly defined composition was established and SULT1A4 as a candidate regulator of mitochondrial homeostasis in hRPC1, offering a standardized preparation route and a potential molecular target for cell-based treatment of retinal degeneration.