Adipose mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p target TLR4 and protect against diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is a complication of diabetes that is increasing in prevalence in China. Extracellular vesicles (EVs) carrying microRNAs (miRs) may represent a useful tool in the development of therapies for DN. Here, we report that EVs released by adipose-derived mesenchymal stem cells (ADSCs) during DN contain a microRNA (miR), miR-26a-5p, that suppresses DN. Using bioinformatic analyses, we identified differentially expressed miRs in EVs from ADSCs and in DN and predicted downstream regulatory target genes. We isolated mesenchymal stem cells (MSCs) from adipose tissues, and collected EVs from the ADSCs. We exposed mouse glomerular podocytes and MP5 cells to high glucose (HG), ADSCs-derived EVs, miR-26a-5p inhibitor/antagomir, Toll-like receptors 4 (TLR4) plasmids, or the NF-κB pathway activator (phorbol-12-myristate-13-acetate, PMA). We used the CCK-8 assay and flow cytometry to investigate the impact of miR-26a-5p on cell viability and apoptosis and validated the results of these assays with in vivo experiments in nude mice. We found that in DN, miR-26a-5p is expressed at very low levels, whereas TLR4 is highly expressed. Of note, EVs from ADSCs ameliorated the pathological symptoms of DN in diabetic mice, and transferred miR-26a-5p to HG-induced MP5 cells, improving viability while suppressing apoptosis of MP5 cells. We also found that miR-26a-5p protects HG-induced MP5 cells from injury by targeting TLR4, inactivating the NF-κB pathway and down-regulating vascular endothelial growth factor A (VEGFA). Moreover, ADSCs-derived EVs transferred miR-26a-5p to mouse glomerular podocytes, which ameliorated DN pathology. These findings suggest that miR-26a-5p from ADSC-derived EVs protects against DN.

Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases

“…Duan et al revealed that the Exo isolated from the conditioned medium of human urine-derived stem cells inhibits the expression of VEGFA and the apoptosis of podocytes by miRNA-16-5p, thereby relieving DN [83]. It is proven by Duan et al that ADSC-EV miRNA-26a-5p suppresses the hyperglycaemiainduced apoptosis of podocytes in mice by downregulating the TLR4 and NF-κB/VEGFA signalling pathways [84]. Anti-fibrosis is also a major mechanism invoked in DN treatment with MSC-EVs.…”

Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

“…Wu et al 19 suggested that miR-100-5p-abundant MSC-exos attenuated cartilage injury via inhibition of mammalian target of rapamycin in osteoarthritis. Duan et al 20 found that adipose mesenchymal stem cell-derived EVs containing miR-26a-5p protected against diabetic nephropathy. In addition, depletion of miRNAs from EVs significantly weakened their regenerative potential in glycerol-induced AKI, suggesting the vital role of miRNA in the therapeutic effect of MSC-EVs 21 .…”

Extracellular Vesicles from Human Adipose-Derived Mesenchymal Stem Cells: A Review of Common Cargos

“…The interest in AT-MSC-EVs has increasingly grown, due to the wide range of AT sources and their relatively easy accessibility [9]. AT-MSC-EVs have been isolated not only from human cells, but also from mouse [24][25][26][27][28][29][30][31][32], rat [33,34], pig [35][36][37][38], and rabbit [39,40] cells. The main objective of most published studies on AT-MSC-EVs was to evaluate their potential use as a new therapeutic approach to treat various diseases.…”