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

doi:10.1038/nm.2490

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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168 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 language	English (US)
Pages (from-to)	1668-1673
Number of pages	6
Journal	Nature Medicine
Volume	17
Issue number	12
DOIs	https://doi.org/10.1038/nm.2490
State	Published - Dec 2011
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.2490

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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

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title = "Stimulating healthy tissue regeneration by targeting the 5-HT 2B 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 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.",

author = "Ebrahimkhani, {Mohammad R.} and Fiona Oakley and Murphy, {Lindsay B.} and Jelena Mann and Anna Moles and Perugorria, {Maria J.} and Elizabeth Ellis and Lakey, {Anne F.} and Burt, {Alastair D.} and Angela Douglass and Wright, {Matthew C.} and White, {Steven A.} and Fabrice Jaffr{\'e} and Luc Maroteaux and Mann, {Derek A.}",

note = "Funding Information: 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.{\textquoteright}s lab is also funded by a European Commission FP7 program grant {\textquoteleft}INFLA-CARE{\textquoteright} (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.{\textquoteright}s work was supported by the Centre National de la Recherche Scientifique, the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale, the Universit{\'e} Pierre et Marie Curie and by grants from the Fondation de France, the Fondation pour la Recherche M{\'e}dicale, the French ministry of research (Agence Nationale pour la Recherche) and the European Commission (DEVANX).",

year = "2011",

month = dec,

doi = "10.1038/nm.2490",

language = "English (US)",

volume = "17",

pages = "1668--1673",

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T1 - Stimulating healthy tissue regeneration by targeting the 5-HT 2B receptor in chronic liver disease

AU - Ebrahimkhani, Mohammad R.

AU - Oakley, Fiona

AU - Murphy, Lindsay B.

AU - Mann, Jelena

AU - Moles, Anna

AU - Perugorria, Maria J.

AU - Ellis, Elizabeth

AU - Lakey, Anne F.

AU - Burt, Alastair D.

AU - Douglass, Angela

AU - Wright, Matthew C.

AU - White, Steven A.

AU - Jaffré, Fabrice

AU - Maroteaux, Luc

AU - Mann, Derek A.

N1 - Funding Information: 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).

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

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Stimulating healthy tissue regeneration by targeting the 5-HT _2B receptor in chronic liver disease

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