Abstract: FR-OR065

Stem Cell-Derived Extracellular Vesicles Protect from VEGF-Induced Endothelial Damage in the Kidney

Session Information

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Sedrakyan, Sargis, Children's hospital Los Angeles, Los Angeles, California, United States
  • De Filippo, Roger E., Children's hospital Los Angeles, Los Angeles, California, United States
  • Bussolati, Benedetta, University of Torino , Torino, Italy
  • Perin, Laura, Children's hospital Los Angeles, Los Angeles, California, United States
  • Villani, Valentina, Children's hospital Los Angeles, Los Angeles, California, United States
  • Da Sacco, Stefano, Children's hospital Los Angeles, Los Angeles, California, United States
  • Tripuraneni, Nikita, Children's hospital Los Angeles, Los Angeles, California, United States
  • Porta, Stefano, University of Torino , Torino, Italy
  • Achena, Andrea, Children's hospital Los Angeles, Los Angeles, California, United States
  • Lavarreda-Pearce, Maria J., Children's hospital Los Angeles, Los Angeles, California, United States
  • Petrosyan, Astgik, Children's hospital Los Angeles, Los Angeles, California, United States
  • Soloyan, Hasmik, Children's hospital Los Angeles, Los Angeles, California, United States
Background

Tight regulation of paracrine VEGF signaling between podocytes and glomerular endothelial cells (GEC) is required for maintenance of the glomerular filtration barrier structure and function. Disruption of VEGF signaling has been implicated in various types of glomerular diseases. However, current therapies neither specifically target the glomerulus nor the local VEGF but in addition, present multiple side effects. Therefore, identification of new approaches that will restore local VEGF signaling remains a potential therapeutic target to treat glomerular disease.

We previously showed that amniotic fluid stem cells (AFSC) are renoprotective in Alport Syndrome (AS), a model of CKD. They home within the diseased glomeruli and secrete extracellular vesicles (EVs). EVs play a key role in stem cell-mediated paracrine function, including the kidney. Herein, we demonstrate that AFSC derived EVs regulate VEGF/VEGFRs signaling balance in AS GEC via a trapping mechanism involving VEGFR1 expressed on the surface of EVs.

Methods

We measured VEGF activity in AS glomeruli by WB. We also assessed VEGF/VEGFRs activity in GEC. We characterized AFSC-EVs cargo by FACS and by miRs arrays and evaluated their potential to affect VEGF biology in GEC and kidney function. EVs silenced for VEGFR1 were used to confirm VEGF trapping by VEGFR1.

Results

Glomeruli from AS mice at 3-months showed increased VEGF activity that was associated with GEC damage and subsequent onset of proteinuria. Treatment with EVs ameliorated the damage and improved kidney function by trapping and sequestration of VEGF. We found VEGFR1, present on the surface of EVs, responsible for this mechanism of action. EVs lacking both the full and soluble VEGFR-1 failed to rescue GEC from VEGF inflicted damage.

Conclusion

We demonstrated for the first time the aberration of VEGF signaling within AS glomeruli. We further showed that AFSC derived EVs play important role in maintaining glomerular homeostasis of VEGF signaling, presenting with a potential for new targeted therapies in CKD.

Funding

  • Private Foundation Support