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

Research output: Contribution to journalArticle

  • Miryam Müller
  • David F Vincent
  • Rachel A Ridgway
  • Elena Lopez-Guadamillas
  • Thomas Jamieson
  • Olivier Govaere
  • Andrew D Campbell
  • 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
  • Alan R Clarke
  • Manuel Serrano
  • Tania A Roskams
  • Owen J Sansom

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  • aan1230_ArticleContent_v9

    Rights statement: Author's peer reviewed manuscript as accepted for publishing.

    Accepted author manuscript, 892 KB, Word document

    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
JournalScience Translational Medicine
Publication statusPublished - 16 Aug 2018


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 twenty four 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 upon macrophage-derived 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 after the current therapeutic window for acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

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