TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

Thomas G. Bird; Miryam Müller; Luke Boulter; David F. Vincent; Rachel A. Ridgway; Elena Lopez-guadamillas; Wei-yu Lu; Thomas Jamieson; Olivier Govaere; Andrew D. Campbell; Sofía Ferreira-gonzalez; Alicia M. Cole; Trevor Hay; Kenneth J. Simpson; William Clark; Ann Hedley; Mairi Clarke; Pauline Gentaz; Colin Nixon; Steven Bryce; Christos Kiourtis; Joep Sprangers; Robert J. B. Nibbs; Nico Van Rooijen; Laurent Bartholin; Steven R. Mcgreal; Udayan Apte; Simon T. Barry; John P. Iredale; Alan R. Clarke; Manuel Serrano; Tania A. Roskams; Owen J. Sansom; Stuart J. Forbes

doi:10.1126/scitranslmed.aan1230

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

Thomas G. Bird, Miryam Müller, Luke Boulter, David F. Vincent, Rachel A. Ridgway, Elena Lopez-guadamillas, Wei-yu Lu, Thomas Jamieson, Olivier Govaere, Andrew D. Campbell, Sofía Ferreira-gonzalez, Alicia M. Cole, Trevor Hay, Kenneth J. Simpson, William Clark, Ann Hedley, Mairi Clarke, Pauline Gentaz, Colin Nixon, Steven BryceChristos Kiourtis, Joep Sprangers, Robert J. B. Nibbs, Nico Van Rooijen, Laurent Bartholin, Steven R. Mcgreal, Udayan Apte, Simon T. Barry, John P. Iredale, Alan R. Clarke, Manuel Serrano, Tania A. Roskams, Owen J. Sansom, Stuart J. Forbes

Immunology and Immunotherapy

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Abstract

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor–β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

Original language	English
Article number	eaan1230
Number of pages	14
Journal	Science Translational Medicine
Volume	10
Issue number	454
DOIs	https://doi.org/10.1126/scitranslmed.aan1230
Publication status	Published - 15 Aug 2018

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Thomas_G_Bird_et_al_TGFβ_inhibition_restores_a_regenerative_response_Science_Translational_Medicine_2018
Checked for eligibility: 12/10/2018 This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on 15 Aug 2018 in Vol. 10, Issue 454, eaan1230, DOI: 10.1126/scitranslmed.aan1230.
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Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-guadamillas, E., Lu, W., Jamieson, T., Govaere, O., Campbell, A. D., Ferreira-gonzalez, S., Cole, A. M., Hay, T., Simpson, K. J., Clark, W., Hedley, A., Clarke, M., Gentaz, P., Nixon, C., ... Forbes, S. J. (2018). TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Science Translational Medicine, 10(454), Article eaan1230. https://doi.org/10.1126/scitranslmed.aan1230

@article{0c929e719a9b4b93857a1f3c5084e4e2,

title = "TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence",

abstract = "Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor–β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.",

author = "Bird, {Thomas G.} and Miryam M{\"u}ller and Luke Boulter and Vincent, {David F.} and Ridgway, {Rachel A.} and Elena Lopez-guadamillas and Wei-yu Lu and Thomas Jamieson and Olivier Govaere and Campbell, {Andrew D.} and Sof{\'i}a Ferreira-gonzalez and Cole, {Alicia M.} and Trevor Hay and Simpson, {Kenneth J.} and William Clark and Ann Hedley and Mairi Clarke and Pauline Gentaz and Colin Nixon and Steven Bryce and Christos Kiourtis and Joep Sprangers and Nibbs, {Robert J. B.} and {Van Rooijen}, Nico and Laurent Bartholin and Mcgreal, {Steven R.} and Udayan Apte and Barry, {Simon T.} and Iredale, {John P.} and Clarke, {Alan R.} and Manuel Serrano and Roskams, {Tania A.} and Sansom, {Owen J.} and Forbes, {Stuart J.}",

year = "2018",

month = aug,

day = "15",

doi = "10.1126/scitranslmed.aan1230",

language = "English",

volume = "10",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "454",

}

Bird, TG, Müller, M, Boulter, L, Vincent, DF, Ridgway, RA, Lopez-guadamillas, E, Lu, W, Jamieson, T, Govaere, O, Campbell, AD, Ferreira-gonzalez, S, Cole, AM, Hay, T, Simpson, KJ, Clark, W, Hedley, A, Clarke, M, Gentaz, P, Nixon, C, Bryce, S, Kiourtis, C, Sprangers, J, Nibbs, RJB, Van Rooijen, N, Bartholin, L, Mcgreal, SR, Apte, U, Barry, ST, Iredale, JP, Clarke, AR, Serrano, M, Roskams, TA, Sansom, OJ & Forbes, SJ 2018, 'TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence', Science Translational Medicine, vol. 10, no. 454, eaan1230. https://doi.org/10.1126/scitranslmed.aan1230

TY - JOUR

T1 - TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

AU - Bird, Thomas G.

AU - Müller, Miryam

AU - Boulter, Luke

AU - Vincent, David F.

AU - Ridgway, Rachel A.

AU - Lopez-guadamillas, Elena

AU - Lu, Wei-yu

AU - Jamieson, Thomas

AU - Govaere, Olivier

AU - Campbell, Andrew D.

AU - Ferreira-gonzalez, Sofía

AU - Cole, Alicia M.

AU - Hay, Trevor

AU - Simpson, Kenneth J.

AU - Clark, William

AU - Hedley, Ann

AU - Clarke, Mairi

AU - Gentaz, Pauline

AU - Nixon, Colin

AU - Bryce, Steven

AU - Kiourtis, Christos

AU - Sprangers, Joep

AU - Nibbs, Robert J. B.

AU - Van Rooijen, Nico

AU - Bartholin, Laurent

AU - Mcgreal, Steven R.

AU - Apte, Udayan

AU - Barry, Simon T.

AU - Iredale, John P.

AU - Clarke, Alan R.

AU - Serrano, Manuel

AU - Roskams, Tania A.

AU - Sansom, Owen J.

AU - Forbes, Stuart J.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor–β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

AB - Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor–β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

U2 - 10.1126/scitranslmed.aan1230

DO - 10.1126/scitranslmed.aan1230

M3 - Article

SN - 1946-6234

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 454

M1 - eaan1230

ER -

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

Abstract

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