Abstract: TH-PO707

Stem-Cell Derived Nano-Extracellular Vesicles Promote Recovery of Diabetic Nephropathy Damaged Kidneys in Mice

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Grange, Cristina, University of Turin, Turin, Italy
  • Bussolati, Benedetta, University of Turin, Turin, Italy
  • Reviriego-Mendoza, Marta, Fresenius Medical Care North America, Waltham, Massachusetts, United States
  • Tetta, Ciro, Fresenius Medical Care North America, Waltham, Massachusetts, United States
  • Maddux, Franklin W., Fresenius Medical Care North America, Waltham, Massachusetts, United States
Background

Nano-Extracellular Vesicles (nEVs) released by stem cells carry transcriptional regulators and secreted RNAs that could be transferred to target cells and induce phenotypic changes. nEVs can reprogram injured cells by activating regenerative processes in acute tissue injury. The aim of this study was to evaluate whether nEVs inhibit chronic kidney injury in a mouse model of diabetic nephropathy (DN).

Methods

To develop ND, NSG mice were injected with 35 mg/Kg of streptozotocin for 4 consecutive days. All treated mice developed diabetes (glycaemia > 250 mg/ml) within 10 days, and DN within 1 month. Mice were intravenously treated with n-EVs derived from human bone marrow stromal cells (MSCs), adipose derived stem cells or liver stem cells (HLSCs) once a week for 5 weeks. Empty n-EVs were used as control[MMRM1] . Kidney function and morphology were evaluated a week later by histological analyses. A comparative bioinformatics analysis of n-EVs-associated miRNAs and proteins was used to identify common anti-fibrotic and pro-regenerative pathways from different kidney cells. The anti-fibrotic effect of n-EVs was analysed by treating mouse kidney fibroblasts in-vitro with TGF-β1 and collagen, and a-sma production.

Results

n-EV treatment resulted in reductions of albumin/creatinine excretion ratio and plasma creatinine, and restoration of urinary acidification when compared to control animals. Histological analyses showed a significant reduction of glomerular and interstitial fibrosis, vascular injury and of Bowman’s space enlargement. Using specific markers, we found significant reduction of cell death and enhanced proliferation in the tubules. All MSC and HLSC stem cell derived n-EVs, but not n-EVs derived from fibroblasts, displayed similar positive effects on reducing DN development. Comparative analyses showed that HLSC and, to a lesser extent MSC n-EVs interfered with the expression of pro-fibrotic miRNAs and inhibited collagen/a-sma production.

Conclusion

We show that n-EVs prevent development of DN in mice by inhibiting fibrosis and promoting regeneration.

Funding

  • Commercial Support