Impaired Function in Diabetic Patient iPSCs-derived Blood Vessel Organoids Stem from a Subpopulation of Vascular Cells

Abstract

The presence of both endothelial cells (ECs) and mural cells are central to the proper function of blood vessels in health and pathological changes in diseases including diabetes. Although iPSCs-derived vascular organoids (VOs) provide an appealing in vitro disease model and platform for drug screening, whether these organoids recapitulate human disease remains debatable. Here, we show human diabetic (DB)-VOs represent impaired vascular function including enhanced ROS activity, with higher mitochondrial content and activity, increased pro-inflammatory cytokines, and less regenerative potential in vivo. Using single-cell RNA sequencing, we identify all specialized types of vascular cells (artery, capillary, vein, lymphatic and tip cells, as well as pericytes and vSMCs) within vascular organoids, while demonstrating the dichotomy landscape of ECs and mural cells. Furthermore, we reveal basal heterogeneity within vascular organoids and demonstrate differences between diabetic and non-diabetic VOs. Of note, a subpopulation of ECs significantly enrich for ROS and oxidative phosphorylation hallmarks in DB-VOs, may represent early signs of aberrant angiogenesis in diabetes. This study helps to identify key biomarkers for diabetic disease progression and find signalling molecules amenable to drug intervention.