Abstract: SA-PO0322
Urine-Derived Stem-Cell Extracellular Vesicles Alleviate Cellular Toxicity Associated with Diabetic Kidney Disease in Human Induced Pluripotent Stem-Cell (iPSC) Models
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Bejoy, Julie, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Hartert, Jack, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Farry, Justin M., Vanderbilt University, Nashville, Tennessee, United States
- Welch, Rick C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Cartailler, Jean-Philippe, Vanderbilt University, Nashville, Tennessee, United States
- Wilson, Matthew H., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Woodard, Lauren Elizabeth, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Group or Team Name
- Woodard Lab.
Background
Poorly controlled diabetes resulting in high blood sugar damages the kidneys, where it disrupts the glomerular filtration barrier including podocytes and endothelial cells. Stem cell and progenitor cells secrete particles called extracellular vesicles (EVs) that carry microRNAs (miRNA), cytokines, and proteins between cells. This study explores whether human urine-derived stem cell EVs (USC-EVs) could reduce cellular injury and apoptosis in the diabetic kidney.
Methods
We injured iPSC-derived human kidney organoids or podocytes with high glucose (HG; 100 mM) for 48 h, followed by treatment with 10 μg of USC-EVs for an additional 48 h before evaluating cell survival, apoptosis, and morphology. We also performed RNA sequencing to determine the miRNAs in USC-EVs together with bioinformatic analysis of the pathways that these miRNAs affect.
Results
We found that HG injury of iPSC-derived podocytes increased apoptosis and reorganization of actin fibers as well as thick deposition of collagen 1 and fibronectin. We treated with USC-EVs and found increased survival of WT1+ podocytes compared to untreated HG podocytes. We next injured organoids with HG, which resulted in degeneration of nephron segments, microvasculature, and the mitochondrial network. We found that HG increased cytotoxicity as measured by lactose dehydrogenase (LDH) release (p< 0.05) and cleaved caspase 3 activity and that HG increased mitochondrial reactive oxygen species and lowered superoxide dismutase (SOD) antioxidant levels. Treating with USC-EVs, we noted preserved nephron markers, improved microvasculature, enhanced SOD activity (p < 0.0001), reduced lipid peroxidation (p < 0.05), and lowered cytotoxicity (p< 0.001) in the organoids. We performed electron microscopy and found fewer necrotic cells in USC-EV-treated organoids. We sequenced miRNAs in the USC-EVs and noted that miR30a-5p, linked to increased podocyte survival in diabetes, was present at high levels.
Conclusion
Taken together, we found that USC-EVs have positive effects in iPSC models of diabetic kidney disease, demonstrating its promise for therapeutic applications. Further research is needed to clarify if the underlying mechanism is reliant upon miRNAs.
Funding
- Veterans Affairs Support