Stimulating Healthy Tissue Regeneration by Targeting the 5-HT₂B Receptor in Chronic Liver Disease

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2011 Nov 29

PMID 22120177

Citations 93

Authors

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 Jaffre

Luc Maroteaux

Derek A Mann

Affiliations

Soon will be listed here.

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.

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