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Cells ; 9(1)2019 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-31861914

RESUMEN

BACKGROUND: Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts, or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several mediators. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1). METHODS: In vivo and in vitro experiments were performed to analyze the expression of OSM and OSM-receptor (OSMR) in three murine models of non-alcoholic-fatty liver disease (NAFLD) and -steatohepatitis (NASH) and in human NASH patients as well as the action of OSM on phenotypic responses of human MFs. RESULTS: Hepatic OSM and OSMR levels were overexpressed in three murine NASH models and in NASH patients. OSM stimulates migration in human MFs by involving early intracellular ROS generation and activation of Ras/Erk, JNK1/2, PI3K/Akt as well as STAT1/STAT3 pathways and HIF-1α. OSM-dependent migration relies on a biphasic mechanism requiring early intracellular generation of reactive oxygen species (ROS) and late HIF1-dependent expression and release of VEGF. CONCLUSION: OSM is overexpressed in experimental and human progressive NAFLD and can act as a profibrogenic factor by directly stimulating migration of hepatic MFs.


Asunto(s)
Miofibroblastos/citología , Enfermedad del Hígado Graso no Alcohólico/genética , Subunidad beta del Receptor de Oncostatina M/genética , Oncostatina M/genética , Regulación hacia Arriba , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Miofibroblastos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oncostatina M/metabolismo , Subunidad beta del Receptor de Oncostatina M/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo
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