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

Abstract

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.

Identification of a global gene expression signature associated with the genetic risk of catastrophic fracture in iPSC-derived osteoblasts from Thoroughbred horses

“…Induced pluripotent stem cells (iPSCs) may provide better cell models due to their ability to differentiate into a wide range of cell types and unlimited growth in vitro. They have been used to study many inherited conditions in humans (Mae et al, 2023, Fear et al, 2023, Gorashi et al, 2023 and are of particular value when access to the affected cell types is limited and/or the cells do not expand well in culture (Pereira et al, 2023). More recently human iPSCs have been used in conjunction with polygenic risk scores (Dobrindt et al, 2021, Coleman, 2022, Yde Ohki et al, 2023 to study the mechanisms underlying complex genetic conditions.…”