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Kidney Week

Abstract: TH-PO800

Extracellular Vesicles Derived from Amniotic Fluid Stem Cells as Potential Therapy for CKD

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Sedrakyan, Sargis, Children's Hospital Los Angeles, Los Angeles, California, United States
  • Villani, Valentina, Children's Hospital Los Angeles, Los Angeles, California, United States
  • Aguiari, Paola, 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
  • Iampietro, Corinne, University of Torino, Torino, Italy
  • Bussolati, Benedetta, University of Torino, Torino, Italy
  • Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
Background

The crosstalk between podocytes and glomerular endothelial cells (GEC) is vital for the maintenance of glomerular function. VEGF signaling plays a key role in the progression of chronic kidney disease (CKD). The discovery of safe therapeutics designed to specifically target the glomerular crosstalk, specifically VEGF signaling, is ground-breaking. We propose that extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) can restore glomerular crosstalk and delay disease progression in Alport Syndrome, a model of CKD.

Methods

GEC were isolated from (Tek-Cre driven) tdT AS and WT mice along disease progression, characterized by WB and RNA-seq with specific focus on VEGF signaling and endothelial damage. EVs were isolated from AFSC, characterized and injected in vivo using our established protocols. Histology and kidney function were evaluated in injected and control mice.

Results

Glomeruli and GEC present with upregulated VEGF signaling before high level of proteinuria. RNA-seq data showed, for the first time, that AS-GEC present with modulation of genes involved in GBM deposition (collagen and laminin) and regulation (MMPs), glycocalyx component (syndecan, perlecan ect), and endothelial markers (VCAM1, ICAM), before the onset of proteinuria. Administration of EVs, at early stage, restore VEGF levels to normal by trapping excessive VEGF (EVs present VEGFR1 and VEGFR2 on the surface) and improve kidney function in AS mice. In light of clinical translation of EVs for CKD, we characterized EVs from human AFSC. We developed specific identity, purity and potency assays that generate EV lots with very similar characteristics between harvests. EVs of human origin present reno-protective activity in vivo in AS mice as well as capability of modulating glomerular VEGF signaling.

Conclusion

Our data suggest that VEGF-induced GEC damage might play a key role in the pathogenesis of AS and its progression and that administration of EVs can delay disease progression by preventing endothelial injury and by restoring to normal VEGF signaling. In sum, our work possibly will facilitate the discovery of new potential glomerulus-specific targeted intervention, thus possibly minimizing disease progression and ameliorating the life of patients affected by CKD.

Funding

  • Private Foundation Support