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.

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration

“…In a mouse model of streptozotocin-induced diabetic nephropathy (DN), multiple (once a week for 4 weeks) intravenous injections of EVs were shown to improve renal function by reversing fibrosis. Array sequencing results showed that the EVs contained high levels of microRNAs, and bioinformatic analyses found that they mainly targeted the biological pathways involved in the profibrotic processes, such as transforming growth factor (TGF)-b, insulin like growth factor 1, EGFR, and PDGFR, which were consistent with the antifibrotic effects exerted by EVs in DN models 77 . In 2016, a clinical trial assessed the safety and therapeutic efficacy of allogeneic hUC-MSC-EVs in the treatment of CKD, including 40 grade III/IV CKD patients, who were randomly divided into two groups.…”

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

“…MSC-sourced miRNAs, particularly let-7c, targeted pro-fibrotic genes (collagen IVα1, TGF-β1 and TGFβR1) in inflamed kidneys, crucially contributing to the therapeutic effects of MSC-EVs in renal fibrosis and diabetic nephropathy [83][84][85]. In line with these findings were results obtained by Zou and colleagues who indicated that MSC-EV-dependent down-regulation of CXCL1 production was responsible for significantly decreased number of CD68+ macrophages in fibrotic kidneys of MSC-EVs-treated mice [84].…”

Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model

“…69 However, the advantages in the use of EVs engineered with Klotho have not been reported yet. In the present study, Klotho was loaded onto fibroblast EVs, a Klotho negative EV source previously described as non-effective in renal repair, 70,71 and the inefficacy of naive EVs in AKI was reverted in parallel with the restoration of its endogenous levels. Moreover, the effect of recombinant Klotho administered alone at a dose comparable with that of uEVs (1 pg/mouse) did not exert any regenerative effect.…”