Stimulating healthy tissue regeneration by targeting the 5-HT 2B receptor in chronic liver disease

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

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113 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)1668-1673
Number of pages6
JournalNature Medicine
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2011

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ebrahimkhani, M. R., Oakley, F., Murphy, L. B., Mann, J., Moles, A., Perugorria, M. J., Ellis, E., Lakey, A. F., Burt, A. D., Douglass, A., Wright, M. C., White, S. A., Jaffré, F., Maroteaux, L., & Mann, D. A. (2011). Stimulating healthy tissue regeneration by targeting the 5-HT 2B receptor in chronic liver disease. Nature Medicine, 17(12), 1668-1673. https://doi.org/10.1038/nm.2490