Hepatic stellate cell–derived platelet‐derived growth factor receptor‐alpha‐enriched extracellular vesicles promote liver fibrosis in mice through SHP2

Abstract

PDGFRα is enriched in EVs derived from PDGF-BB-treated HSCs in an Src homology 2 domain tyrosine phosphatase 2-dependent manner and these PDGFRα-enriched EVs participate in development of liver fibrosis. (Hepatology 2018;68:333-348).

Extracellular vesicles, the liquid biopsy of the future

“…10 From non-parenchymal cells, activated HSC-EVs promote neighboring HSC migration and regulate fibrogenesis. 11,12 In the bile, Hep-EVs and cholangiocyte-derived EVs are mediators of cholangiocyte proliferation. 13 These studies demonstrate that liver cell-derived EVs may be important contributors to hepatic regeneration, inflammation, angiogenesis and fibrosis.…”

“…They are reported to contain proteins and microRNAs important for disease progression. 2,8,11,12,[14][15][16] Bile EVs have been examined in the context of cholangiocarcinoma, with microRNAs being the center of attention of most of these investigations. 2 Some of these EV-associated markers have been studied in patients with liver disease.…”

Extracellular vesicles: Future diagnostic and therapeutic tools for liver disease and regeneration

“…HSC are also producing EV, thereby amplifying the fibrosis process through an action on HSC or on other non‐parenchymal cells. Kostallari et al demonstrated that primary and lineage HSC (LX2) sequestrated PDGFRα into EV after cell incubation with its ligand PDGF‐BB, a cytokine known to be implicated in liver fibrosis . Such EV promoted HSC migration in vitro but also liver fibrosis in vivo and were isolated from blood of patients with liver fibrosis.…”

Extracellular Vesicles in Liver Diseases: Meeting Report from the International Liver Congress 2018

“…Accordingly, numerous liver conditions have been evaluated in terms of their EV profile and pathobiological relevance, including, among others, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic hepatitis (AH), cirrhosis, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and other cholangiopathies (such as primary sclerosing cholangitis [PSC]). In the liver, hepatocytes, immune cells, endothelial cells, hepatic stellate cells (HSCs), and cholangiocytes all contribute to EV production …”

“…In the liver, hepatocytes, immune cells, endothelial cells, hepatic stellate cells (HSCs), and cholangiocytes all contribute to EV production. (22)(23)(24)(25) NAFLD and NASH Lipotoxicity, a process by which accumulation of certain toxic lipids (e.g., saturated free fatty acids) in hepatocytes triggers various molecular pathways of cell stress and eventually results in cell death, has evolved as a key event along NAFLD progression to NASH and eventually to HCC. (4) During the process of lipotoxicity, hepatocytes release large numbers of EVs that may act on different target cells and contribute to key processes involved in NAFLD pathogenesis, including immune modulation, angiogenesis, and fibrosis ( Fig.…”