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Stimulating healthy tissue regeneration by targeting the 5-HT_2B receptor in chronic liver disease

Lookup NU author(s): Dr Mohammed Ebrahimkhani, Professor Fiona OakleyORCiD, Dr Lindsay Murphy, Professor Jelena Mann, Dr Maria Perugorria, Dr Elizabeth Ellis, Anne Lakey, Professor Alastair BurtORCiD, Dr Andrew Douglass, Professor Matthew Wright, Professor Derek Mann

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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(1). 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 beta 1 (TGF-beta 1), 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.

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Author(s): Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, Ellis E, Lakey AF, Burt AD, Douglass A, Wright MC, White SA, Jaffre F, Maroteaux L, Mann DA

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2011

Volume: 17

Issue: 12

Pages: 1668-U189

Print publication date: 27/11/2011

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nm.2490

DOI: 10.1038/nm.2490

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