HLSC-Derived Extracellular Vesicles Attenuate Liver Fibrosis and Inflammation in a Murine Model of Non-alcoholic Steatohepatitis

Abstract

Extracellular vesicles (EVs) are membrane vesicles released virtually by all cell types. Several studies have shown that stem cellderived EVs may mimic both in vitro and in vivo the biological effects of the cells. We recently demonstrated that non-alcoholic steatohepatitis (NASH) is inhibited by treatment with human liver stem cells (HLSCs). The aim of the present study was to evaluate whether EVs released by HLSCs influence the progression of NASH, induced by a diet deprived of methionine and choline, in immunocompromised mice. EV treatment was initiated after 2 weeks of diet with a biweekly administration of three different doses. Bio-distribution evaluated by optical imaging showed a preferential accumulation in normal and, in particular, in fibrotic liver. EV treatment significantly improved liver function and reduced signs of liver fibrosis and inflammation at both morphological and molecular levels. In particular, we observed that, out of 29 fibrosis-associated genes upregulated in NASH liver, 28 were significantly downregulated by EV treatment. In conclusion, HLSC-derived EVs display anti-fibrotic and antiinflammatory effects in a model of chronic liver disease, leading to an improvement of liver function.

Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model

“…The animals were distributed into four groups: (1) the SHAM group-the rats were submitted to surgical procedures without the ischemic injury; (2) the IRI group-the rats were submitted to bilateral renal arterial clamping (45 min) followed by reperfusion with immediate subcapsular injection of PBS into each kidney after removal of the clamps; (3) the IRI+ iPSC-EV group-the rats were submitted to bilateral renal arterial clamping and received subcapsular injection on both kidneys of 1 × 10 9 EV derived from iPSC at the beginning of reperfusion in each kidney; (4) the IRI+ASC-EV group-the rats were submitted to the same surgical procedures followed by subcapsular injection into each kidney of 1 × 10 9 EV derived from ASC. The doses of EV were defined on the basis of previous works [8,18,19] and from other works wherein MSC-EV promoted protective effects in different kidney injury models. The subcapsular injection was chosen to observe a direct effect of EV in the kidney and to guarantee the delivery of the entire amount of EV.…”

Extracellular Vesicles From Hepatocytes Are Therapeutic for Toxin-Mediated Fibrosis and Gene Expression in the Liver

“…Finally, many studies have started to emerge showing that toxic liver injury, inflammation, hepatic fibrosis and HSC activation are ameliorated by EVs produced by various stem cells (SC) including umbilical cord mesenchymal SC (Li et al, 2013;Jiang et al, 2018), adipose-derived mesenchymal SC (Qu et al, 2017), embryonic SC-derived mesenchymal stromal cells (Mardpour et al, 2018), amnion-derived mesenchymal SC (Ohara et al, 2018), pluripotent SC (Povero et al, 2019), bone marrow mesenchymal SC (Rong et al, 2019), and liver SC (Bruno et al, 2019). As this research area expands, it will be important to determine if common mechanisms in these EV populations account for their shared therapeutic effects in the liver and the extent to which there is mechanistic overlap with antifibrogenic EVs from differentiated cells such as either hepatocytes as reported here or quiescent HSC as reported previously (Chen et al, 2014(Chen et al, , 2015(Chen et al, , 2016b.…”

Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation

“…HSC fibrogenesis is stimulated by these types of hepatocyte-derived EVs [29,32,41], while other phenotypic features of activated HSC such as migration and AKT phosphorylation have been shown to be enhanced by EVs from liver sinusoidal endothelial cells [42]. On the other hand, EVs from healthy hepatocytes [43], various stem cells [44][45][46][47][48][49][50][51] or the serum of healthy mice [52] have the ability to inhibit experimental liver fibrosis, largely by suppressing inflammatory responses and/or pathways of activation or fibrogenesis in HSC. The recognition that HSC are EV targets has highlighted an important new mechanism by which fibrogenic pathways in the liver are modulated and has given a new lead for novel anti-fibrotic therapies based on suppressing the action of pro-fibrotic EVs or harnessing the actions of EVs that are intrinsically anti-fibrotic.…”