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Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy.

ABSTRACT: Extracellular vesicles (EVs) that are derived from mesenchymal stromal cells (MSCs) have been shown to reprogram injured cells by activating regenerative processes. We herein investigate the potential therapeutic effect of EVs, shed by human bone marrow MSCs and by human liver stem-like cells (HLSCs), on the progression and reversion of fibrosis in a mouse model of diabetic nephropathy, as induced by streptozotocin. After the development of nephropathy, stem cell-derived EVs were administered weekly to diabetic mice for four weeks. The stem cell-derived EV treatment, but not the fibroblast EV treatment that was used as a control, significantly ameliorated functional parameters, such as albumin/creatinine excretion, plasma creatinine and blood urea nitrogen, which are altered in diabetic mice. Moreover, the renal fibrosis that develops during diabetic nephropathy progression was significantly inhibited in stem cell EV-treated animals. A correlation was found between the down regulation of several pro-fibrotic genes in renal tissues and the anti-fibrotic effect of HLSC and MSC EVs. A comparative analysis of HLSC and MSC EV miRNA content highlighted some common and some specific patterns of miRNAs that target predicted pro-fibrotic genes. In conclusion, stem cell-derived EVs inhibit fibrosis and prevent its progression in a model of diabetes-induced chronic kidney injury.

SUBMITTER: Grange C

PROVIDER: S-EPMC6418239 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy.

Grange Cristina C Tritta Stefania S Tapparo Marta M Cedrino Massimo M Tetta Ciro C Camussi Giovanni G Brizzi Maria Felice MF

Scientific reports 20190314 1

Extracellular vesicles (EVs) that are derived from mesenchymal stromal cells (MSCs) have been shown to reprogram injured cells by activating regenerative processes. We herein investigate the potential therapeutic effect of EVs, shed by human bone marrow MSCs and by human liver stem-like cells (HLSCs), on the progression and reversion of fibrosis in a mouse model of diabetic nephropathy, as induced by streptozotocin. After the development of nephropathy, stem cell-derived EVs were administered we ...[more]

PMID: 30872726

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Project description:IntroductionEarly initiation is essential for successful treatment of Fabry disease, but sensitive and noninvasive biomarkers of Fabry nephropathy are lacking. Urinary extracellular vesicles (uEVs) represent a promising source of biomarkers of kidney involvement. Among them, microRNAs (miRNAs) are important post-transcriptional regulators of gene expression that contribute to the development and progression of various kidney diseases. We aimed to identify uEV-derived miRNAs involved in the development and/or progression of Fabry nephropathy.MethodsPatients with genetically confirmed Fabry disease and matched control subjects were included. EVs were isolated from the second morning urine by size exclusion chromatography, from which miRNAs were extracted. miRNA urine exosome PCR panels were used to characterize the miRNA signature in a discovery cohort. Individual qPCRs were performed on a validation cohort that included chronological samples. We identified the target genes of dysregulated miRNAs and searched for potential hub genes. Enrichment analyses were performed to identify their potential function.ResultsThe expression of miR-21-5p and miR-222-3p was significantly higher in patients with stable renal function and those with progressive nephropathy compared with the corresponding controls. In addition, the expression of miR-30a-5p, miR-10b-5p, and miR-204-5p was significantly lower in patients with progressive nephropathy, however, in the chronological samples, this was only confirmed for miR-204-5p. Some of the identified hub genes controlled by the dysregulated miRNAs have been associated with kidney impairment in other kidney diseases.ConclusionThe miRNA cargo in uEVs changes with the development and progression of Fabry nephropathy and, therefore, represents a potential biomarker that may provide a new option to prevent or attenuate the progression of nephropathy. Furthermore, dysregulated miRNAs were shown to be potentially associated with pathophysiological pathways in the kidney.

Dataset Information

Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy.

Publications

Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy.

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