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dc.contributor.authorEbrahimkhani, M.-
dc.contributor.authorOakley, F.-
dc.contributor.authorMurphy, L.-
dc.contributor.authorMann, J.-
dc.contributor.authorMoles, A.-
dc.contributor.authorPerugorria, M.-
dc.contributor.authorEllis, E.-
dc.contributor.authorLakey, A.-
dc.contributor.authorBurt, A.-
dc.contributor.authorDouglass, A.-
dc.contributor.authorWright, M.-
dc.contributor.authorWhite, S.-
dc.contributor.authorJaffre, F.-
dc.contributor.authorMaroteaux, L.-
dc.contributor.authorMann, D.-
dc.identifier.citationNature Medicine, 2011; 17(12):1668-1673-
dc.description.abstractTissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood1. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT2B is clinically safe in humans and may be therapeutic in chronic liver disease.-
dc.description.statementofresponsibilityMohammad R Ebrahimkhani, Fiona Oakley, Lindsay B Murphy, Jelena Mann, Anna Moles, Maria J Perugorria, Elizabeth Ellis, Anne F Lakey, Alastair D Burt, Angela Douglass, Matthew C Wright, Steven A White, Fabrice Jaffré, Luc Maroteaux & Derek A Mann-
dc.publisherNature Publishing Group-
dc.rightsCopyright status unknown-
dc.subjectCells, Cultured-
dc.subjectMice, Inbred C57BL-
dc.subjectMice, Knockout-
dc.subjectRats, Sprague-Dawley-
dc.subjectLiver Cirrhosis-
dc.subjectChronic Disease-
dc.subjectMitogen-Activated Protein Kinase 1-
dc.subjectProto-Oncogene Proteins c-jun-
dc.subjectReceptor, Serotonin, 5-HT2B-
dc.subjectElectrophoresis, Polyacrylamide Gel-
dc.subjectWound Healing-
dc.subjectSignal Transduction-
dc.subjectCell Proliferation-
dc.subjectTransforming Growth Factor beta1-
dc.subjectHepatic Stellate Cells-
dc.subjectSerotonin 5-HT2 Receptor Antagonists-
dc.titleStimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease-
dc.title.alternativeStimulating healthy tissue regeneration by targeting the 5-HT(2B) receptor in chronic liver disease-
dc.typeJournal article-
dc.identifier.orcidBurt, A. [0000-0002-3011-7774]-
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