Organotypic vascularization improves maturation of human stem cell-derived islets and restores normoglycemia in diabetic mice.

Human pluripotent stem cells-derived pancreatic islet organoids (PIOs) hold promise for treating type 1 diabetes, but poor post-transplant survival due to inadequate vascularization remains a major challenge. Here, we generated vascularized PIOs (VPIOs) by co-culturing PIOs with blood vessel organoids (BVOs), resulting in integrated structures with BVOs-derived capillary networks that penetrate into the islet structures. These blood vessels structurally exhibit fenestrations characteristic of islet-specific endothelium and carry a molecular signature of organotypic vasculature. β cells within the VPIOs display partially enhanced maturation and greater resistance to hypoxia and endoplasmic reticulum stress. Following subcutaneous transplantation into diabetic mice, VPIOs exhibit markedly improved survival, establish vascular connections with the host circulation, and restore long-term normoglycemia. Our work presents a strategy for generating vascularized islet organoids that enhances β cell maturation and tissue-specific blood vessel specification in vitro and, critically, improves graft survival and function in vivo.