Abstract
Introduction: Diabetes is one of the major risk factors for cardiovascular diseases (CVDs), which is mediated by vascular endothelial dysfunction. Currently, there is no in vitro disease model of endothelial cell (EC) dysfunction in diabetic patients, which hinders mechanistic understanding and therapeutic discovery. The goal of this study is to develop a comprehensive model of diabetic EC dysfunction using patient-derived induced pluripotent stem cells (iPSCs) and recapitulating the diabetic microenvironment. Methods: Our model utilizes iPSC derived ECs from the following sources: healthy subjects and diabetic patients with underlying CVDs (n=3). To simulate in situ conditions of diabetes, we used the following treatment for 5 days: hyperglycemia (25 mM glucose); high urea (9 mM); and inflammatory stimulation with tumor necrosis factor alpha (TNF-α, 8 pg/ml). EC dysfunction was assessed through oxidative stress, inflammation, permeability, and thrombosis. Immunofluorescence identified localization for surface adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), endothelial selectin (E-sel), and platelet selectin (P-sel). Enzyme-linked immunosorbent assay (ELISA) quantitatively measured expression of these surface adhesion molecules. Results: Overall, the qualitative effect of the diabetic microenvironment resulted in increased expression of ICAM-1, E-sel, and P-sel. After TNF-α treatment, we observed a stronger increase in expression of P-sel in healthy subject-derived cells than diabetic patient-derived cells. This indicates a possible pre-conditioned tolerance of pro-inflammatory conditions. Ongoing experimentation will provide results for quantitative expression of ICAM-1, E-sel, and P-sel after treatment with the diabetic microenvironment. Conclusion: The development of a robust in vitro model of diabetic endothelial dysfunction, similar to the onset of type 2 diabetes, will allow for high-throughput testing of pharmacological agents to ultimately treat the disease’s effects within the vascular bed. The widespread implications of type 2 diabetes on the vascular bed further amplify the significance of this study in the development of pharmacological agents to treat the disease.
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