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Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease

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.

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Figure 1: Selective depletion of hepatic stellate cells or antagonism of 5-HT2B stimulates liver growth.
Figure 2: Gene deletion or blockade of 5-HT2B enhances liver regeneration after PHX.
Figure 3: 5-HT2B blockade enhances liver regeneration by inhibiting induction of TGF-β1 expression by HSC that is dependent on 5-HT, ERK and JunD.
Figure 4: Blockade of 5-HT2B receptors attenuates liver fibrosis.

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Acknowledgements

This work was funded by grants from the UK Medical Research Council (grant G0700890 to D.A.M., M.C.W. and F.O. and G0900535 to F.O.), the Wellcome Trust (grant WT084961MA to F.O., D.A.M. and M.C.W. and WT086755MA to M.C.W., A.D.B. and D.A.M.). Work in D.A.M.'s lab is also funded by a European Commission FP7 program grant 'INFLA-CARE' (EC Contract No. 223151; http://inflacare.imbb.forth.gr/). M.R.E. was supported by a European Association for Study of the Liver (EASL) Sheila Sherlock fellowship. L.M.'s work was supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the French ministry of research (Agence Nationale pour la Recherche) and the European Commission (DEVANX).

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Contributions

M.R.E. and F.O. performed the majority of the experiments with assistance from L.B.M., J.M., E.E., A.D., M.C.W., F.J., A.M., M.J.P., A.F.L. and L.M. A.D.B. determined the fibrosis scores in the mouse models of liver injury. S.A.W. supplied the human liver tissue for the isolation of hepatocytes and stellate cells. D.A.M. and F.O. conceived of the study, planned the experiments and wrote the paper.

Corresponding author

Correspondence to Derek A Mann.

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M.C.W. has a financial interest in any commercial use of C1-3 through the licensing agreements of a previous employer but takes no part in and has no influence on any commercialization activities.

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Ebrahimkhani, M., Oakley, F., Murphy, L. et al. Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease. Nat Med 17, 1668–1673 (2011). https://doi.org/10.1038/nm.2490

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