Extracellular Vesicles and Chronic Kidney Disease

Presented at: Cell Biology 2020
C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Assistant Professor of Urology, Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California
    Biography

      Sargis Sedrakyan, Ph.D. is a Children's Hospital Los Angeles and Saban Research Institute Investigator and Assistant Professor of Urology at the University of Southern California. Dr. Sedrakyan received his undergraduate degree in Biology at Brooklyn College, the City University of New York, his Ph.D. in Stem Cells and Regenerative Medicine from University of Padua, Italy and completed a postdoctoral research training in Developmental Biology and Regenerative Medicine at The Saban Research Institute, Children's Hospital Los Angeles and the University of Southern California. His research focuses on understanding the etiology and development of chronic kidney diseases, with an emphasis on the functional role of glomerular endothelial cells, and the development of stem cell-derived extracellular vesicle based applications to treat kidney disease. 


    Abstract

    Chronic kidney disease (CKD) is a major public health threat, affecting 11-15% of the U.S. population alone. Currently, there are no effective therapies to cure CKD. Drug therapies are not potent, and directed only at slowing deterioration of renal function and treating metabolic consequences of CKD. With end-stage renal disease (ESRD) the only options are dialysis or transplantation.  To address the large unmet need for CKD therapies we identified potent renal protective effects of amniotic fluid stem cell derived extracellular vesicles (AFSC-EVs) in preclinical studies. AFSC-EVs are uniquely suited and represent an innovative therapeutic strategy for treatment of CKD. Using Alport syndrome (AS) as a model of CKD, we have previously shown that administration of amniotic fluid stem cells (AFSC) provides therapeutic value, improves renal function and prolongs animal survival. We established that the beneficial effect of AFSC is mainly attributed to secretion of extacellular vesicles (EVs) that contribute to the paracrine activity of AFSC in the kidney, and that administration of EVs alone recapitulate the protective effects of AFSC providing functional and survival benefits. AFSC-EVs are characterized by an array of exosomal and mesenchymal surface markers and miRNA cargo typical to the cell of their origin. In light of potential translation to treat CKD, in addition to mouse lines we characterized EVs derived from human AFSC. We have established that hAFSC are genotypically stable, can be easily scaled up and are high producers of EV. We have reduced EV heterogeneity by use of human clonal cell lines of AFSC, which can produce EVs with comparable expression profile and efficacy in vivo in our animal model of CKD, suggesting high reproducibility. We developed specific identity and potency assays thus guaranteeing the generation of lots of EVs with similar characteristics for therapeutic application. We performed extensive characterization of clonally derived EVs by proteomic and miRNA-seq analysis and using hollow fiber bioreactor system we are also able to increase EV production to clinical scale without losing characteristic purity, potency and efficacy. In order to advance the translation of hEVs and to explore their safety, targeting and effectiveness, we also developed a state of the art in vivo monitoring capabilities using novel magnetic nanoparticle agent for labeling EVs to study EV biodistribution by means of MRI technology. Our biodistribution studies showed that when injected in vivo into AS mice, hAFSC-EVs localized in the kidney, corrected proteinuria and prolonged the life-span of treated mice. In conclusion, we strongly believe that our findings will significantly enhance the development of EVs for paracrine regulation of glomerular diseases, with potential implications for patients affected by CKD.

    Learning Objectives:

    1. To understand the structure and function of the glomerulus, development of chronic kidney disease  and the pathophysiology of Alport syndrome

    2. To understand the characterization of functional extracellular vesicles using in vitro and in vivo models, and potential imaging strategies for live tracking of EVs in vivo


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