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The role of extracellular vesicles from different cellular sources in modulation of hepatic stellate cell biology and liver fibrosis
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Akiko Eguchi1,
Ariel E Feldstein2,
Yoshiyuki Takei1 |
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1Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2Department of Pediatrics, University of California San Diego |
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| Hepatocyte-derived extracellular vesicles (HC-EVs) are involved in the progression of liver diseases via activation of hepatic stellate cells (HSCs). In contrast, mesenchymal stem cell-derived EVs attenuate the tissue injury. Here we showed that number of circulating EVs and HC-EVs were significantly increased in alcoholic hepatitis (AH) mice. AH-HC-EVs encapsulated 24 miRNAs with significant changes including profibrogenic miRNAs resulted in HSC activation. Several genes involved in HSC activation were predicted targets of 17 miRNAs up-regulated in AH-HC-EVs. Indeed, Nr1d2 as quiescence marker were reduced in HSC transfected with miR-27a and miR-181. These results suggest that AH-HC-EVs orchestrate liver fibrogenesis by directly targeting HSC quiescence transcripts via a unique set of miRNAs. EV specific cargo may represent novel therapeutic targets, although it may difficult to suppress specific EV-miRNAs in vivo. Therefore, we investigate the effect of induced pluripotent stem cell (iPSC)-derived EV on HSC modulation and liver fibrosis in vitro and in vivo. iPSC-derived EVs were isolated from human iPSCs generated by reprogramming primary skin fibroblast. iPSC-EVs internalized in HSC resulted in decrease of profibrogenic genes and HSC profibrogenic responses. Intravenous injection of iPSC-EVs in CCl4-induced and bile duct ligation-induced liver fibrosis resulted in antifibrotic effects. These results identified iPSC-EVs as potentially novel antifibrotic approach that may reduce or reverse liver fibrosis in patients with chronic liver disease. |
Index Term 1: extracellular vesicles
Index Term 2: liver fibrosis
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