In Vitro Modeling of Atherosclerosis Using iPSC-Derived Blood Vessel Organoids.

Abstract

As modeling of atherosclerosis requires recapitulating complex interactions with vasculature and immune cells, previous in vitro models have limitations due to their insufficient 3D vascular structures. However, induced pluripotent stem cell-derived blood vessel organoids (BVOs) are applicable for modeling vascular diseases, containing multiple cell types, including endothelial and vascular smooth muscle cells self-assembled into a blood vessel structure. Atherosclerotic BVOs with a microenvironment associated with atherogenesis, such as shear stress, low-density lipoprotein, pro-inflammatory cytokine, and monocyte co-culture are successfully developed. In atherosclerotic BVOs, representative atherosclerotic phenotypes, including endothelial dysfunction, inflammatory responses, formation of foam cells and fibrous plaque, and moreover, calcification of the plaques are observed. To verify the drug response in this model, it is treated with clinically used lovastatin and confirm phenotype attenuation. Furthermore, the therapeutic efficacy of nano-sized graphene oxides (NGOs) is evaluated on atherosclerosis. Due to their anti-inflammatory effects, NGOs effectively alleviate the pathologic lesions in atherosclerotic BVOs by promoting macrophage polarization toward M2. These results suggest that atherosclerotic BVOs are advanced in vitro models suitable for drug discovery and elucidation of therapeutic mechanisms. From the perspective of precision medicine, this platform using patient-derived BVOs can be further employed for personalized drug screening in the future.