title: Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease.
abstract: Tissue 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 understood. 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-HT(2B)) 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-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.
authors: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors: Mohammad R
authors: MR
authors: Ebrahimkhani
authors: Fiona
authors: F
authors: Oakley
authors: Lindsay B
authors: LB
authors: Murphy
authors: Jelena
authors: J
authors: Mann
authors: Anna
authors: A
authors: Moles
authors: Maria J
authors: MJ
authors: Perugorria
authors: Elizabeth
authors: E
authors: Ellis
authors: Anne F
authors: AF
authors: Lakey
authors: Alastair D
authors: AD
authors: Burt
authors: Angela
authors: A
authors: Douglass
authors: Matthew C
authors: MC
authors: Wright
authors: Steven A
authors: SA
authors: White
authors: Fabrice
authors: F
authors: Jaffré
authors: Luc
authors: L
authors: Maroteaux
authors: Derek A
authors: DA
authors: Mann
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004591:Electrophoresis, Polyacrylamide Gel; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014945:Wound Healing
chemical_list: D007211:Indoles; C549531:JunD protein, rat; C092756:N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea; D016755:Proto-Oncogene Proteins c-jun; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D053773:Transforming Growth Factor beta1; C528955:junD protein, mouse; D012701:Serotonin; D014508:Urea; D019950:Mitogen-Activated Protein Kinase 1