Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

Abstract

Hepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 × 109 particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-α, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 × 109 particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 × 109 HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.

Human liver stem cell‐derived extracellular vesicles reduce injury in a model of normothermic machine perfusion of rat livers previously exposed to a prolonged warm ischemia

“…Nonetheless, these preliminary findings must be interpreted considering some limitations. First, we did not observe significant differences in the RNA levels of the targets evaluated in this study, despite our previous experience on several pathways modulated by HLSCs in different models of liver injury [29,53,54]. On the basis of some trends observed in the expression of genes related to endothelial cell activation (VCAM‐1, P‐Selectin, and E‐Selectin), we investigated their expression also at the protein level but again there were no significant changes among the study groups.…”

miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2

“…BMMSC-derived exosomes have been shown to reduce liver IR injury by regulating the inflammatory response [ 8 ]. The exosomes from MSCs induced by human pluripotent stem cells and exosomes from human liver stem cells both have a protective effect on liver IRI [ 39 , 40 ]. Our previous study found that HO-1/BMMSC-exosomes can reduce the inflammatory injury of intestinal epithelial cells and improve the structure of intercellular tight junction proteins, which is an important mechanism by which HO-1/BMMSCs play a protective role [ 10 ].…”

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

“…These data indicate that treatment with HLSC-EVs immediately after renal IRI protects the kidney from developing fibrosis by modulating the expression levels of specific genes that are involved in fibrosis and the EMT process. Moreover, it has recently been reported that HLSC-EVs protect the liver from IRI by modulating the gene expression of key inflammatory molecules [46]. Although these results hold great promise for a possible therapeutic approach against kidney injury, the complex mechanism by which HLSC-EVs can interfere with AKI and subsequently CKD development, remains to be elucidated.…”