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

ABSTRACT: Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs), followed by matrix deposition. Recently, several studies have shown the importance of extracellular vesicles (EVs) derived from liver cells, such as hepatocytes and endothelial cells, in liver pathobiology. While most of the studies describe how liver cells modulate HSC behavior, an important gap exists in the understanding of HSC-derived signals and more specifically HSC-derived EVs in liver fibrosis. Here, we investigated the molecules released through HSC-derived EVs, the mechanism of their release, and the role of these EVs in fibrosis. Mass spectrometric analysis showed that platelet-derived growth factor (PDGF) receptor-alpha (PDGFR?) was enriched in EVs derived from PDGF-BB-treated HSCs. Moreover, patients with liver fibrosis had increased PDGFR? levels in serum EVs compared to healthy individuals. Mechanistically, in vitro tyrosine720-to-phenylalanine mutation on the PDGFR? sequence abolished enrichment of PDGFR? in EVs and redirected the receptor toward degradation. Congruently, the inhibition of Src homology 2 domain tyrosine phosphatase 2, the regulatory binding partner of phosphorylated tyrosine720, also inhibited PDGFR? enrichment in EVs. EVs derived from PDGFR?-overexpressing cells promoted in vitro HSC migration and in vivo liver fibrosis. Finally, administration of Src homology 2 domain tyrosine phosphatase 2inhibitor, SHP099, to carbon tetrachloride-administered mice inhibited PDGFR? enrichment in serum EVs and reduced liver fibrosis. CONCLUSION:PDGFR? is enriched in EVs derived from PDGF-BB-treated HSCs in an Src homology 2 domain tyrosine phosphatase 2-dependent manner and these PDGFR?-enriched EVs participate in development of liver fibrosis. (Hepatology 2018;68:333-348).

PROVIDER: S-EPMC6033667 | BioStudies |

REPOSITORIES: biostudies

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