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Abstract: FR-PO764

Uremic Vasculopathy Modeling with Induced Pluripotent Stem Cells and Uremic Toxin Mixtures

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Jang, Hye Ryoun, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Lee, Kyungho, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Boo, Hyo jin, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Kim, Suhyun, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Lee, Jung eun, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Huh, Wooseong, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Kim, Dae joong, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yoon-Goo, Stem cells and Regenerative Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
Background

Cardiovascular complications remain as major causes of morbidity and mortality in end-stage renal disease (ESRD) patients. Although uremic vasculopathy substantially contributes to the development of cardiovascular complications in ESRD, it is difficult to simulate uremic vasculopathy with current research methods like animal models or cell culture experiment. In this study, we aimed to develop a simplified uremic vasculopathy model using uremic toxin mixtures on endothelial cells differentiated from induced pluripotent stem cells (iPSCs-ECs).

Methods

Peripheral blood mononuclear cells from a normal control and an ESRD patient was reprogrammed to iPSCs using Sendai virus, then iPSC-ECs were differentiated from iPSCs. Uremic toxin mixtures comprised of diverse combination of urea, creatinine, uric acid, indoxyl sulfate, and advanced glycation end-product were tested in a cell culture model of iPSC-ECs. Reactive oxygen species (ROS), apoptosis, and tube formation or scratch migration assay were measured to evaluate dysfunction of iPSC-ECs. Media alone was used as a negative control and 15% serum from ESRD patients receiving hemodialysis was used as a positive control.

Results

Urea, uric acid, and indoxyl sulfate significantly suppressed the tube formation of iPSC-ECs, while creatinine alone did not affect ROS levels or the tube formation of iPSC-ECs. Uremic toxin mixtures comprised of high concentration of urea, creatinine, uric acid, and indoxyl sulfate increased ROS production and apoptosis, whereas decreased tube formation of iPSC-ECs similarly with ESRD patients’ uremic serum. ESRD patient-specific iPSC-ECs showed impaired wound healing potential which was partially restored by losartan and TGF-β inhibitor.

Conclusion

We developed a simplified uremic vasculopathy model using uremic toxin mixtures comprised of urea, uric acid, and indoxyl sulfate and iPSC-ECs. This novel model may be used as a new research tool of uremic vasculopathy and drug screening system.