Modeling Moyamoya disease using patient-derived induced pluripotent stem cells and organoids.

The underlying mechanisms of Moyamoya disease (MMD), a rare, progressive cerebrovascular disorder marked by distal internal carotid artery stenosis or occlusion and the formation of fragile collaterals, remain poorly understood, in part because conventional models fail to capture the genetic, vascular, and neurovascular complexity of human MMD. Driven by recent advances in disease modeling, MMD research has moved beyond early endothelial progenitor cell studies toward patient-derived induced pluripotent stem cell (iPSC)-based platforms. Here, we summarize the generation and validation of MMD-specific iPSCs and their differentiation into endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and related vascular lineages, and we discuss how two-dimensional (2D) iPSC-based models have provided insights into impaired angiogenesis, endothelial dysfunction, abnormal VSMC behavior, and disrupted vascular cell interactions. We then highlight the emerging use of three-dimensional vascular and neurovascular organoids, which reproduce cellular heterogeneity, vessel-like organization, and neurovascular unit interactions more closely than conventional 2D cultures. These models may provide a more integrated platform for investigating the complex vascular pathophysiology of MMD. Finally, we discuss future directions for MMD modeling, including the integration of multi-omics profiling and CRISPR-mediated genome editing with patient-derived iPSC and organoid platforms. These approaches may help clarify genotype-phenotype relationships, RNF213-dependent and RNF213-independent mechanisms, and disease-relevant molecular pathways. With further standardization and validation, iPSC- and organoid-based models could support mechanistic studies, therapeutic screening, and personalized disease modeling. Our review underscores the emerging role of patient-derived stem cell and organoid technologies in advancing MMD research and in informing future translational efforts.