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

• Published in: International journal of molecular sciences Vol. 23; no. 3; p. 1485
• Main Authors: Bruno, Stefania, Chiabotto, Giulia, Cedrino, Massimo, Ceccotti, Elena, Pasquino, Chiara, De Rosa, Samuela, Grange, Cristina, Tritta, Stefania, Camussi, Giovanni
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.01.2022; MDPI
• Subjects: acute kidney injury; Animals; chronic kidney disease; Collagen; Creatinine; epithelial-to-mesenchymal transition; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - transplantation; Fibrosis; Gene expression; Genes; Hepatocytes; Histology; Humans; Inflammation; Injury analysis; Ischemia; Kidney diseases; Liver; Liver - metabolism; Liver - pathology; Male; Mesenchyme; Mice; Mice, Inbred BALB C; Morphology; renal fibrosis; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - therapy; Reperfusion; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - therapy; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Surgery; Tumor necrosis factor-TNF; Vesicles; chronic kidney disease; acute kidney injury; renal fibrosis; epithelial-to-mesenchymal transition
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031485

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.