The critical roles of hemodynamic cues, including shear stress and perfusion, together with metabolic and immune signaling, in driving the coordinated maturation of endothelial and mural compartments are highlighted.
Abstract
Human vascular function depends on tightly coordinated structural, mechanical, and cellular interactions, yet these features remain difficult to recapitulate in vitro. Induced pluripotent stem cells (iPSCs) enable efficient generation of vascular cell types, including endothelial cells, smooth muscle cells, and pericytes, but current systems often lack functional maturity and physiological relevance. Recent advances in vascular organoid engineering provide new opportunities to address this limitation. By integrating self-organization, co-culture, and bioengineering approaches, iPSC-derived systems can form three-dimensional vascular networks with increasing physiological relevance. Emerging evidence from studies of iPSC-derived vascular systems, spanning both two-dimensional differentiation models and three-dimensional organoid platforms, highlights the critical roles of hemodynamic cues, including shear stress and perfusion, together with metabolic and immune signaling, in driving the coordinated maturation of endothelial and mural compartments. These platforms enable modeling of key vascular pathologies, including inflammation, vascular remodeling, and barrier dysfunction, while gene editing further facilitates mechanistic investigation in patient-specific contexts. Together, iPSC-derived vascular systems provide a scalable and physiologically relevant platform for disease modeling, drug discovery, and regenerative medicine.
This review systematically summarizes the roles of various stem cells in angiogenesis, outlines strategies for constructing vascularized organoids, and highlights their emerging applications in modeling vascular-associated diseases and regenerative therapy, providing a comprehensive reference for advancing both basic research and clinical translation in vascular medicine.
Qiuyue Gao, Cai-Feng Long, An-Jun Zhong et al.· Global Translational Medicin...· 0 citations
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.
Traditional human blood vessel organoids, built primarily around endothelial monocultures, fail to replicate the multicellular architecture and dynamic immunological functions of native microvasculature. This review synthesizes an emerging paradigm shift toward third-generation, multi-lineage, and immune-competent vascular organoids. Multicellular integration, combining perivascular mural lineages (pericytes and vascular smooth muscle cells) with functional immune populations (macrophages, microglia, and lymphocytes), is delineated. Its role in reinstating baseline barrier tightness, contractility, and tissue-level immunosurveillance is highlighted. Critical bioengineering workflows are examined, with emphasis on fluidic shear stress in microfluidic platforms, the spatial precision afforded by three-dimensional (3D) bioprinting, and multiplex CRISPR gene editing. These technologies resolve lineage-specific media conflicts and enable off-the-shelf, hypoimmunogenic vascular constructs. Furthermore, the capacity of these systems to recapitulate complex pathophysiology is evaluated. Such pathophysiology includes complement-driven immunothrombosis in SARS-CoV-2 infection, neurovascular degeneration in Alzheimer’s disease, genetic small-vessel disorders, and tumor-immune barriers that govern chimeric antigen receptor T (CAR-T) cell infiltration. Finally, persistent translational hurdles are outlined, including metabolic bottlenecks, diffusion limits, scale‑up challenges, and the lack of large‑animal efficacy and safety data. Strategies that may help transition these models from research tools toward clinically relevant platforms are also discussed.
Vascularized liver organoids are developed by integrating human induced pluripotent stem cell (iPSC)–derived hepatoblasts and endothelial cells into decellularized scaffolds functionalized with an anti-CD31 aptamer–based vascular coating agent (VCA) to establish a comprehensive framework for generating physiologically relevant liver tissues from iPSCs and demonstrate the utility of spatial transcriptomics for uncovering regenerative mechanisms.
Da-Hyun Kim, Yongju Lee, Min-Ji Kim et al.· Science Advances· 1 citation
Vascular organoids derived from human pluripotent stem cells (hPSCs) have emerged as powerful three-dimensional models for studying vascular development, disease mechanisms, and drug responses. Current vascular organoid protocols enable the generation of self-organizing endothelial-pericyte networks; however, batch-to-batch variability, inconsistent organoid formation, and inadequate pericyte coverage can compromise reproducibility and scalability. This study presents an optimized protocol for generating vascular organoids from human induced pluripotent stem cells (hiPSCs) with improved reproducibility and structural consistency. Key modifications include refined embryoid body formation conditions, optimized growth factor concentrations and timing during mesoderm induction and vascular specification, and improved three-dimensional culture conditions that promote robust pericyte recruitment and endothelial-pericyte interactions. The optimized organoids exhibit highly branched CD31-positive endothelial networks consistently ensheathed by PDGFR-β-positive pericytes, with significantly reduced batch-to-batch variability compared with the original protocol. Detailed, step-by-step procedures are provided for organoid generation, whole-mount immunofluorescence characterization, and quality control assessment. This optimized method enables the scalable production of high-quality vascular organoids suitable for studying vascular cell interactions, modeling disease, and screening compounds, thereby lowering the technical barrier for laboratories seeking to adopt this model system.
Unknown authors· Journal of Visualized Experi...· 0 citations
A function-first framework in which regenerative organoids are engineered and evaluated according to measurable therapeutic outcomes, including tissue-specific function, vascular integration, immune compatibility, reproducibility, scalability, and long-term stability is proposed.
Yusuke Nishimura· Stem Cells· 0 citations
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