Generation of Self‐Organizing Macrovascular Constructs by Bioprinting Human iPSC‐Derived Mesodermal Progenitor Cells

ABSTRACT Vascularization remains a major obstacle in tissue engineering. Here, we introduce a bioprinting strategy to generate centimeter‐scale, self‐organizing “mother vessel” constructs from iPSC‐derived hiMPCs. By optimizing bioink composition, printing was accomplished in a single‐step approach. Within one week, hiMPCs differentiated into both CD31 + endothelial and αSMA + mural cells, driving the morphogenesis of the vessel wall comprising intima, media and adventitia. The remaining hiMPCs formed a mesodermal tissue around the vessel wall. Remarkably, CD34 + , CD150 + , and IBA1 + progenitors were detected within the mother vessel construct. The vessel wall reached a median thickness of approximately 150 µm within the first 10 days and exhibited collagen III and elastic fibers. Furthermore, eNOS expression was detected in endothelial cells. Co‐culture of the “mother vessel” with prevascularized organoids resulted in interconnection between organoid‐derived microvessels and those of the mother vessel. Angiogenic sprouts extended into the surrounding mesodermal tissue. Monocyte adhesion to luminal endothelial cells was significantly increased following TNFα stimulation. After integration into a bioreactor, the mother vessel withstood applied flow without detectable leakage. In summary, we established a developmentally inspired platform that bridges macro‐ and microvascularization. This approach may pave the way toward perfusable, vascularized large‐scale tissue constructs, addressing a major bottleneck in regenerative biofabrication.