Background: Extracellular Vesicles (EVs) released by stem cells carry several bioactive molecules such as proteins and RNA (mRNAs and miRNAs) that could be transferred to target cells inducing phenotypic changes. EVs can reprogram injured cells by activating regenerative processes in acute tissue injury. The aim of this study was to evaluate whether EVs inhibit the progression of chronic kidney injury in a mouse model of diabetic nephropathy (DN). Methods: To develop DN, 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 EVs derived from human bone marrow mesenchymal stromal cells (MSCs), or human adult liver stem cells (HLSCs) once a week for 4 weeks. Kidney function were evaluated by analysing blood and urine for physiological parameters and tissues for morphological studies. A comparative EV bioinformatic analysis was performed to identify potential anti-fibrotic and pro-regenerative miRNAs. Results: EV treatments resulted in significant amelioration of physiological parameters such as reduction of albumin/creatinine excretion ratio and plasma creatinine compared to control DN mice. Moreover, a restoration of urinary acidification was observed when mice received EV injection. Histological analyses revealed a significant reduction of glomerular and interstitial fibrosis, Bowman’s space enlargement and tubular damage. Conclusions: This study provides evidence for a therapeutic effect of MSC- and HLSC-derived EVs on the progression of DN. This effect likely relies on EV mediated inhibition of fibrosis.
Stem-Cell Derived Extracellular Vesicles Promote Recovery of Diabetic Nephropathy Damaged Kidneys in Mice
Cristina Grange;Benedetta Bussolati;Ciro Tetta;
2017-01-01
Abstract
Background: Extracellular Vesicles (EVs) released by stem cells carry several bioactive molecules such as proteins and RNA (mRNAs and miRNAs) that could be transferred to target cells inducing phenotypic changes. EVs can reprogram injured cells by activating regenerative processes in acute tissue injury. The aim of this study was to evaluate whether EVs inhibit the progression of chronic kidney injury in a mouse model of diabetic nephropathy (DN). Methods: To develop DN, 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 EVs derived from human bone marrow mesenchymal stromal cells (MSCs), or human adult liver stem cells (HLSCs) once a week for 4 weeks. Kidney function were evaluated by analysing blood and urine for physiological parameters and tissues for morphological studies. A comparative EV bioinformatic analysis was performed to identify potential anti-fibrotic and pro-regenerative miRNAs. Results: EV treatments resulted in significant amelioration of physiological parameters such as reduction of albumin/creatinine excretion ratio and plasma creatinine compared to control DN mice. Moreover, a restoration of urinary acidification was observed when mice received EV injection. Histological analyses revealed a significant reduction of glomerular and interstitial fibrosis, Bowman’s space enlargement and tubular damage. Conclusions: This study provides evidence for a therapeutic effect of MSC- and HLSC-derived EVs on the progression of DN. This effect likely relies on EV mediated inhibition of fibrosis.
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