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Kidney Week

Abstract: SA-PO338

Regeneration-Associated Cell-Derived Extracellular Vesicles Preserve Kidney Function After Acute Ischemia Injury

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Salybekov, Amankeldi, Shonan Kamakura Sogo Byoin, Kamakura, Kanagawa, Japan
  • Okamura, Shigeaki, Shonan Kamakura Sogo Byoin, Kamakura, Kanagawa, Japan
  • Hidaka, Sumi, Shonan Kamakura Sogo Byoin, Kamakura, Kanagawa, Japan
  • Ohtake, Takayasu, Shonan Kamakura Sogo Byoin, Kamakura, Kanagawa, Japan
  • Asahara, Takayuki, Shonan Kamakura Sogo Byoin, Kamakura, Kanagawa, Japan
  • Kobayashi, Shuzo, Shonan Kamakura Sogo Byoin, Kamakura, Kanagawa, Japan
Background

Under vasculogenic conditioning, pro-inflammatory cell subsets of peripheral blood mononuclear cells (PBMCs) shift their phenotype to pro-regenerative cells such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells, collectively designated as regeneration-associated cells (RACs). In this study, we evaluated the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared with a vehicle-treated group using the rat kidney ischemia-reperfusion injury (K-IRI) model.

Methods

Human PBMCs were cultured with defined growth factors for seven and then two days to harvest RACs and RAC-ev, respectively. EV sizes were characterized by nanoparticle tracking analysis. Transmission electron microscopy revealed a bi-layered membrane structure and flow cytometry confirmed the presence of EV-specific markers (CD9, CD63, and Alix).

Results

Notably, systemic injection of RACev significantly decreased serum creatinine and blood urine nitrogen (P < 0.01 and P < 0.005) at day three after the onset of K-IRI than the control group. Histologically, the treatment group showed less fibrosis in the cortex and medullary areas (P < 0.04 and P < 0.01) compared to the control group. CD31 staining confirmed enhanced capillary densities at the cortex and medullary areas in the treatment group compared to the control group (P < 0.003). These beneficial effects were coupled with significant expression of angiogenesis (miR-126-3p/5p, miR-195-3p/5p, miR-146-3p/5p), anti-fibrosis (miR-133a-3p, miR-29b-3p), anti-inflammation (miR-10a-3p, miR-21-3p, miR-24-2p), and anti-apoptosis miRs by RACev. In vivo bioluminescence analysis showed preferential accumulation of RACev in the IR-injured kidney.

Conclusion

In conclusion, systemic transplantation of RACev improved kidney function via protecting from tissue fibrosis, anti-inflammation, and angiogenesis miR delivery to the ischemic tissue.