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Type: Journal article
Title: Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease
Other Titles: Stimulating healthy tissue regeneration by targeting the 5-HT(2B) receptor in chronic liver disease
Author: Ebrahimkhani, M.
Oakley, F.
Murphy, L.
Mann, J.
Moles, A.
Perugorria, M.
Ellis, E.
Lakey, A.
Burt, A.
Douglass, A.
Wright, M.
White, S.
Jaffre, F.
Maroteaux, L.
Mann, D.
Citation: Nature Medicine, 2011; 17(12):1668-1673
Publisher: Nature Publishing Group
Issue Date: 2011
ISSN: 1078-8956
Statement of
Mohammad 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
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 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.
Keywords: Cells, Cultured
Mice, Inbred C57BL
Mice, Knockout
Rats, Sprague-Dawley
Liver Cirrhosis
Chronic Disease
Mitogen-Activated Protein Kinase 1
Proto-Oncogene Proteins c-jun
Receptor, Serotonin, 5-HT2B
Electrophoresis, Polyacrylamide Gel
Wound Healing
Signal Transduction
Cell Proliferation
Transforming Growth Factor beta1
Hepatic Stellate Cells
Serotonin 5-HT2 Receptor Antagonists
Description: Letters
Rights: Copyright status unknown
DOI: 10.1038/nm.2490
Published version:
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