Unraveling new players in helminth pathology: extracellular vesicles from Fasciola hepatica and Dicrocoelium dendriticum exert different effects on hepatic stellate cells and hepatocytes

• Published in: International journal for parasitology Vol. 54; no. 12; pp. 617 - 634
• Main Authors: Sánchez-López, Christian M., González-Arce, Aránzazu, Ramírez-Toledo, Víctor, Bernal, Dolores, Marcilla, Antonio
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-10-2024
• Subjects: Animals; Dicrocoeliasis - parasitology; Dicrocoelium; Dicrocoelium dendriticum; Extracellular Vesicles - metabolism; Fasciola hepatica; Fasciola hepatica - physiology; Fascioliasis - parasitology; Fibrosis; Helminth EVs; Hepatic stellate cells; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - parasitology; Hepatocytes; Hepatocytes - parasitology; Humans; Dicrocoelium dendriticum; Fasciola hepatica; Hepatic stellate cells; Hepatocytes; Helminth EVs; Fibrosis
• ISSN: 0020-7519; 1879-0135; 1879-0135
• DOI: 10.1016/j.ijpara.2024.06.002

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•Fasciola hepatica extracellular vesicles (HpEVs) induce extracellular matrix secretion.•HpEVs reduce proliferation of hepatic stellate cells (HSCs)•Dicrocoelium dendriticum EVs (DdEVs) trigger a global inflammatory response in HSCs and hepatocytes.•DdEVs have a more potent anti-proliferative effect than FhEVs.•FhEVs are taken up faster and in higher amounts than DdEVs by HSCs and hepatocytes.
Fasciola hepatica and Dicrocoelium dendriticum are parasitic trematodes residing in the bile ducts of mammalian hosts, causing, in some cases, impairment of liver function and hepatic fibrosis. Previous studies have shown that extracellular vesicles released by F. hepatica (FhEVs) and D. dendriticum (DdEVs) induce a distinct phenotype in human macrophages, but there is limited information on the effect of parasitic EVs on liver cells, which interact directly with the worms in natural infections. In this study, we isolated FhEVs and DdEVs by size exclusion chromatography and labeled them with a lipophilic fluorescent dye to analyze their uptake by human hepatic stellate cells (HSC) and hepatocytes, important cell types in liver pathology, using synthetic liposomes as internal labeling and uptake control. We analyzed EV uptake and the proteome profiles after the treatment with EVs for both cell types. Our results reveal that EVs establish unique and specific interactions with stellate cells and hepatocytes, suggesting a different role of EVs derived from each parasite, depending on the migration route to reach their final niche. FhEVs have a cytostatic effect on HSCs, but induce the extracellular matrix secretion and elicit anti-inflammatory responses in hepatocytes. DdEVs have a more potent anti-proliferative effect than FhEVs and trigger a global inflammatory response, increasing the levels of NF-κB and other inflammatory mediators in both cell types. These interactions may have a major influence on the progression of the disease, serving to generate conditions that may favor the establishment of the helminths in the host.