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.
Highlights
Diabetic nephropathy (DN), a long-term diabetes complication, is the most common cause of end-stage chronic kidney disease (CKD) and has a high mortality rate[1]
Previous studies have demonstrated that human liver stem-like cells (HLSCs), a multipotent population of adult stem cells derived from human livers that express mesenchymal stromal cells (MSCs) and embryonic markers, release extracellular vesicles (EVs) with pro-regenerative activity, in the liver, and in the kidney[19,26,27]
EVs derived from stem cells purified from human urine, have been described as effective in the prevention of kidney injury by inhibiting apoptosis when administered before the establishment of DN, in a rat model of diabetes generated via streptozotocin (STZ) injection[28]
Summary
Diabetic nephropathy (DN), a long-term diabetes complication, is the most common cause of end-stage chronic kidney disease (CKD) and has a high mortality rate[1]. The transforming growth factor β (TGF-β) superfamily plays a significant role in modulating fibrosis[10] In this scenario, novel therapeutic strategies that can prevent the decline of renal function and reduce the progression of fibrosis are in high demand. Kholia et al.[25] have recently shown that EVs, derived from human liver stem-like cells (HLSCs), significantly inhibit reductions in renal function and prevent fibrosis in a model of aristolochic-acid-induced CKD. Previous studies have demonstrated that HLSCs, a multipotent population of adult stem cells derived from human livers that express MSC and embryonic markers, release EVs with pro-regenerative activity, in the liver, and in the kidney[19,26,27]. The aim of this study is to investigate whether EVs, released by human bone marrow MSCs and HLSCs, may be beneficial in preventing and reverting DN progression in NOD/SCID/IL2Rγ KO (NSG) mice
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