Modular Assembly of Arterial Organoids Enables Rapid Blood Perfusion to Ameliorate Ischemic Diseases
Transplantation of vascular cells remains a promising therapeutic strategy for enhancing vascular regeneration in the treatment of ischemic diseases. However, its clinical translation is hindered by poor engraftment and limited reparative potential. Here, we established a scalable methodology for generating suspensible, homogeneous arterial organoids (AOs) from human iPSCs using a three-dimensional bioreactor system. These spheroidal AOs constituted micron-scale vascular modules, enveloped by a confluent layer of arterial-like endothelial cells interfaced with mural cells. Local injection prompted the assembly of the modules into a larger tube, where the interstitial spaces between them constituted interconnected channels that supported rapid perfusion. To evaluate the therapeutic potential of this approach, we applied AOs in murine models of hindlimb ischemia and myocardial infarction. Upon delivery, the AOs rapidly anastomosed with the host vasculature, enhancing perfusion recovery and preserving tissue function, thereby outperforming single-cell counterparts. Mechanistically, the implanted AOs further recruited VEGFA-secreting macrophages to remodel the microenvironment, further reinforcing vascular regeneration. Collectively, our findings demonstrate that AOs can self-organize into perfusable vascular networks in vivo to restore blood flow in ischemic tissues. This study establishes injectable AOs as a promising therapeutic platform for the treatment of ischemic diseases.