Modeling diabetic endothelial dysfunction with patient-specific induced pluripotent stem cells

Diabetes is a known risk factor for various cardiovascular complications, mediated by endothelial dysfunction. Despite the high prevalence of this metabolic disorder, there is a lack of in vitro models that recapitulate the complexity of genetic and environmental factors associated with diabetic endothelial dysfunction. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to develop in vitro models of diabetic endothelial dysfunction. We found that the diabetic phenotype was recapitulated in diabetic patient-derived iPSC-ECs, even in the absence of a diabetogenic environment. Subsequent exposure to culture conditions that mimic the diabetic clinical chemistry induced a diabetic phenotype in healthy iPSC-ECs but did not affect the already dysfunctional diabetic iPSC-ECs. RNA-seq analysis revealed extensive transcriptome-wide differences between cells derived from healthy individuals and diabetic patients. The in vitro disease models were used as a screening platform which identified angiotensin receptor blockers (ARBs) that improved endothelial function in vitro for each patient. In summary, we present in vitro models of diabetic endothelial dysfunction using iPSC technology, taking into account the complexity of genetic and environmental factors in the metabolic disorder. Our study provides novel insights into the pathophysiology of diabetic endothelial dysfunction and highlights the potential of iPSC-based models for drug discovery and personalized medicine.

Automated summary

Diabetes is a risk factor for cardiovascular complications due to endothelial dysfunction. In this study, human iPSC-derived endothelial cells were used to create in vitro models of diabetic endothelial dysfunction, replicating the diabetic phenotype in diabetic patient-derived iPSC-ECs. Culturing healthy iPSC-ECs under diabetic conditions induced a diabetic phenotype, while already dysfunctional diabetic iPSC-ECs were unaffected. These models were used to identify angiotensin receptor blockers that improved endothelial function for each patient, demonstrating the potential of iPSC-based models for drug discovery and personalized medicine.