Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System

Frontiers in Cell and Developmental Biology

Ning-Yi Shao¹  Hyung Joon Cho²  Jung Eun Lee²  Sang-Ging Ong²  Yoon-Goo Kim²  Wooseong Huh³  Hye Ryoun Jang⁴  Junseok Jeon⁴  Won Hee Lee⁴  Hoai Huong Thi Le⁵  Yang Zhou⁶  Kyungho Lee⁷ 

[1] Energy, Arizona State University, Tempe, AZ, United States;Regenerative Medicine Institute(SCRMI), Sungkyunkwan University School of Medicine, Seoul, South Korea;Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, United States;;Division of Nephrology, Department of Medicine, Samsung Medical Center, Stem Cell &Health Sciences, University of Macau, Macau, China;;School for Engineering of Matter, Transport &Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States;

关键词: endothelial cells;    induced pluripotent stem cells;    uremic vasculopathy;    uremic toxin;    chronic kidney disease;   

DOI  :  10.3389/fcell.2020.618796

来源: DOAJ

【 摘 要 】

Background: Cardiovascular complications are the leading cause of mortality in patients with chronic kidney disease (CKD). Uremic vasculopathy plays a crucial role in facilitating the progression of cardiovascular complications in advanced CKD. However, the improvement of conventional research methods could provide further insights into CKD.Objectives: In this study, we aimed to develop a novel model of uremic vasculopathy as a potential drug screening system.Methods and Results: The effects of uremic serum and different combinations of uremic toxins on induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) of a normal control and a CKD patient were investigated using several functional assays. We found that a mixture of uremic toxins composed of high urea, creatinine, uric acid, and indoxyl sulfate exerted deleterious effects on normal control iPSC-ECs that were comparable to uremic serum by increasing reactive oxygen species and apoptosis, as well as suppression of tube formation. Additional characterization revealed a potential involvement of dysregulated TGF-β signaling as treatment with either losartan or TGF-β inhibitors led to the attenuation of adverse effects induced by uremic toxins. Importantly, impaired wound healing potential seen in CKD patient-specific iPSC-ECs was rescued by treatment with losartan and TGF-β inhibitors.Conclusion: Our study demonstrated that simplified uremic toxin mixtures can simulate the uremic micromilieu reproducibly and CKD patient-specific iPSC-ECs can potentially recapitulate susceptibility to uremic vasculopathy. This novel model of uremic vasculopathy may provide a new research tool as a drug screening system.

【 授权许可】

Unknown