Amniotic fluid stem cell-derived vesicles protect from VEGF-induced endothelial damage

• Published in: Scientific reports Vol. 7; no. 1; pp. 16875 - 12
• Main Authors: Sedrakyan, S., Villani, V., Da Sacco, S., Tripuraneni, N., Porta, S., Achena, A., Lavarreda-Pearce, M., Petrosyan, A., Soloyan, H., Filippo, R. E. De, Bussolati, B., Perin, L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2017; Nature Publishing Group
• Subjects: 13/100; 13/106; 631/532/2063; 631/61/2320; 631/61/51/1844/2319; Alport syndrome; Amniotic fluid; Amniotic Fluid - cytology; Animals; Cell surface; Cells, Cultured; Coculture Techniques; Creatinine - blood; Disease Models, Animal; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Extracellular Vesicles - metabolism; Fibrosis; Glomerulus; Humanities and Social Sciences; Kidney Glomerulus - cytology; Mice; multidisciplinary; Nephritis, Hereditary - metabolism; Nephritis, Hereditary - pathology; Proteinuria - pathology; Rodents; Science; Science (multidisciplinary); Signal Transduction; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Trapping; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vesicles
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-17061-2

Injection of amniotic fluid stem cells (AFSC) delays the course of progression of renal fibrosis in animals with Alport Syndrome, enhancing kidney function and improving survival. The mechanisms responsible for these protective outcomes are still largely unknown. Here, we showed that vascular endothelial growth factor (VEGF) signaling within the glomeruli of Alport mice is strongly elevated early on in the disease, causing glomerular endothelial cell damage. Intraventricular injected AFSC that homed within the glomeruli showed strong modulation of the VEGF activity, particularly in glomerular endothelial cells. To investigate this phenomenon we hypothesized that extracellular vesicles (EVs) produced by the AFSC could be responsible for the observed renoprotection. AFSC derived EVs presented exosomal and stem cell markers on their surface membrane, including VEGFR1 and VEGFR2. EVs were able to modulate VEGF in glomerular endothelial cells by effectively trapping the excess VEGF through VEGFR1-binding preventing cellular damage. In contrast, VEGFR1/sVEGFR1 knockout EVs failed to show similar protection, thus indicating that VEGF trapping is a potentially viable mechanism for AFSC-EV mediated renoprotection. Taken together, our findings establish that EVs secreted by AFSC could target a specific signaling pathway within the glomerulus, thus representing a new potential glomerulus-specific targeted intervention.