Human iPSC-derived vascularized organoids: strategy-based insights from 2D endothelial cells to 3D blood vessel organoids

Abstract

Organoids derived from human pluripotent stem cells (PSCs) have emerged as powerful in vitro models for studying development, disease, and therapeutic responses, yet their lack of functional vasculature limits growth, maturation, and physiological relevance. Early vascularization strategies relied on human umbilical vein endothelial cells (ECs), which lack organ-specific identity and introduce donor variability. The field is now undergoing a paradigm shift toward PSC-derived vasculature, which offers patient-specific, and developmentally stage-matched endothelium with PSC-derived organoids. This review summarizes current strategies for organoid vascularization, with emphasis on both human PSC-derived 2D ECs and 3D blood vessels. Approaches relying on co-aggregation of differentiated ECs with organ-specific populations or external endothelial coating of pre-formed organoids. These improved survival and functional maturation but remain limited in spatial organization and perfusability. The advances have incorporated pre-formed vascular spheroids and iPSC-derived blood vessel organoids, which can be respectively fused with lineage-specific organoids to generate vascularized assembloids to enhance vascular architecture and tissue maturation. This review further highlights engineering the microenvironment to promote the formation of vascular niche, such as hypoxia modulation, transcriptional regulation, signaling transduction, and extracellular matrix engineering. In addition, we discuss the current limitations as well as future directions of vascularized organoids, including the unmet need for developing tissue-specific ECs, improved engraftment following transplantation, and organ-on-a-chip platforms. Collectively, integrating iPSC-derived vasculature within organoids provides a central framework toward physiologically relevant, perfusable tissues and expands the translational utility of organoid technologies for disease modeling and therapeutic development.