Extracellular Vesicles Derived from Human Liver Stem Cells Attenuate Chronic Kidney Disease Development in an In Vivo Experimental Model of Renal Ischemia and Reperfusion Injury

Abstract

The potential therapeutic effect of extracellular vesicles (EVs) that are derived from human liver stem cells (HLSCs) has been tested in an in vivo model of renal ischemia and reperfusion injury (IRI), that induce the development of chronic kidney disease (CKD). EVs were administered intravenously immediately after the IRI and three days later, then their effect was tested at different time points to evaluate how EV-treatment might interfere with fibrosis development. In IRI-mice that were sacrificed two months after the injury, EV- treatment decreased the development of interstitial fibrosis at the histological and molecular levels. Furthermore, the expression levels of pro-inflammatory genes and of epithelial–mesenchymal transition (EMT) genes were significantly reverted by EV-treatment. In IRI-mice that were sacrificed at early time points (two and three days after the injury), functional and histological analyses showed that EV-treatment induced an amelioration of the acute kidney injury (AKI) that was induced by IRI. Interestingly, at the molecular level, a reduction of pro-fibrotic and EMT-genes in sacrificed IRI-mice was observed at days two and three after the injury. These data indicate that in renal IRI, treatment with HLSC-derived EVs improves AKI and interferes with the development of subsequent CKD by modulating the genes that are involved in fibrosis and EMT.

Upregulation of miR145 and miR126 in EVs from Renal Cells Undergoing EMT and Urine of Diabetic Nephropathy Patients

“…The grids were then incubated with 2.5% glutaraldehyde plus 2% sucrose. EVs were negatively stained with NanoVan (Nanoprobes, Yaphank, NY, USA) and observed using a Jeol JEM 1400 Flash electron microscope (Jeol, Tokyo, Japan) [ 37 ].…”

Bibliometric analysis of scientific papers on extracellular vesicles in kidney disease published between 1999 and 2022

“…Camussi Giovanni (corresponding author) from the Department of Medical Sciences, University of Turin, was the top 5 prolific author for EVs in kidney disease. He mainly focused on the association of EVs with kidney-related diseases (AKI, CKD, systemic lupus erythematosus, ANCA-vasculitis, kidney fibrosis, and diabetic nephropathy) ( Biancone and Camussi, 2014 ; Collino et al, 2015 ; Lener et al, 2015 ; Bussolati and Camussi, 2017 ; Dimuccio et al, 2020 ; Grange et al, 2020 ; Kholia et al, 2020 ; Ramírez-Bajo et al, 2020 ; Tetta et al, 2020 ; Kholia et al, 2021 ; Mazzariol et al, 2021 ; Bruno et al, 2022 ; Franzin et al, 2022 ). Additionally, Cortes Raquel (corresponding author) from the Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, was the top 4 prolific author for EVs in kidney-related diseases.…”

Naïve or Engineered Extracellular Vesicles from Different Cell Sources: Therapeutic Tools for Kidney Diseases

“…Multiple pathophysiological alterations occur in association with AKI such as glomerular hyper-filtration, proteinuria, tubular sclerosis, and interstitial inflammation leading to the progressive decline of renal function and morphology [ 43 ]. Considering the severity of the damage and the incidence of other health problems there is an increased risk of a maladaptive repair after AKI which predisposes to the progression to CKD [ 44 ] ( Figure 2 ).…”

“…In a murine model of IRI-induced AKI which subsequently developed into CKD, two intravenous injections of HLSC-EVs interfered with CKD development by effectively reducing interstitial fibrosis, the infiltration of inflammatory cells, and by down-regulating the gene expression levels of pro-fibrotic and pro-inflammatory markers, such as α-Sma, Col1a1, Tumor Necrosis Factor-α (TNF-α) and interleukin-6 (IL-6) [ 44 ].…”