Abstract: TH-PO329

Regenerative Effects of Stem Cell Derived Nano-Extracellular Vesicles in AKI in Mice

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Tetta, Ciro, Fresenius Medical Care, Waltham, Massachusetts, United States
  • Gau, Daniel, Unicyte AG, Oberdorf, Switzerland
  • Larkin, John W., Fresenius Medical Care North America, Waltham, Massachusetts, United States
  • Maddux, Franklin W., Fresenius Medical Care North America, Waltham, Massachusetts, United States
Background

The use of nano-extracellular vesicles (n-EVs) to treat several pathologies including cancers, inflammatory and heart disease has increased in the recent years (Ref). Various adult stem cells, including mesenchymal stromal cells (MSCs) and human liver stem cells (HLSCs), are known to promote regeneration involving n-EVs. We studied the regenerative potential of MSC- and HLSC-derived n-EVs in acute kidney injury (AKI) models.

Methods

We utilized two mouse models of AKI: glycerol-induced in severe-combined immune-deficient (SCID) mice and an ischemia reperfusion injury (IRI) model. One IV injection of n-EVs was administered 3 days after induction of AKI. The study was also performed in vitro using HLSC derived EV cell model of IRI induced by ATP depletion. miRNA-depleted n-EVs from MSCs were created by knocking down Drosha as a negative control.

Results

In glycerol-induced AKI, both MSC- and HLSC-derived n-EV injections accelerated injured kidney recovery. n-EVs localized only in injured kidney cells. In the IRI model, MSC n-EV treatment prevented damage and inhibited chronic functional and morphological sequelae. n-EVs treatment up-regulated anti-apoptotic genes (BCL-XL, BIRC8 & BCL2), down-regulated pro-apoptotic genes (LTA, CASP1 & CASP8), and inhibited transcription of pro-inflammatory genes, extracellular matrix-receptor interaction, cell adhesion molecules, and inhibition of cell cycle. In an HLSC EV model of IRI, n-EV administration reverted RNA changes in renal tubular epithelial cells and inhibited tubular cell apoptosis. In a miRNA-depleted n-EV model, the n-EV’s protective effect in AKI was significantly decreased. MSC n-EVs treatment significantly improved survival in a lethal model of cisplatin-induced AKI in SCID mice.

Conclusion

The findings indicate that MSC- and HLSC- derived n-EVs have regenerative effects in AKI mouse models. n-EVs may be promising for the development of stem cell free therapies.

Funding

  • Commercial Support