Activated hepatic stellate cells: Negative regulators of... : Hepatology (original) (raw)
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Activated hepatic stellate cells: Negative regulators of hepatocyte proliferation in liver diseases
Chung, Chuhan M.D.1; Iwakiri, Yasuko Ph.D.1; Groszmann, Roberto J.†,a; Iwakiri, Yasuko†,a; Taddei, Tamar H.†,a
1_Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT_
†New Haven, CT
a_†_
Received 9 February 2012; Accepted 26 March 2012
Potential conflict of interest: Nothing to report.
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-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.
Copyright © 2012 American Association for the Study of Liver Diseases.