RT Journal Article SR Electronic T1 TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence JF Science Translational Medicine FD American Association for the Advancement of Science SP eaan1230 DO 10.1126/scitranslmed.aan1230 VO 10 IS 454 A1 Bird, Thomas G. A1 Müller, Miryam A1 Boulter, Luke A1 Vincent, David F. A1 Ridgway, Rachel A. A1 Lopez-Guadamillas, Elena A1 Lu, Wei-Yu A1 Jamieson, Thomas A1 Govaere, Olivier A1 Campbell, Andrew D. A1 Ferreira-Gonzalez, Sofía A1 Cole, Alicia M. A1 Hay, Trevor A1 Simpson, Kenneth J. A1 Clark, William A1 Hedley, Ann A1 Clarke, Mairi A1 Gentaz, Pauline A1 Nixon, Colin A1 Bryce, Steven A1 Kiourtis, Christos A1 Sprangers, Joep A1 Nibbs, Robert J. B. A1 Van Rooijen, Nico A1 Bartholin, Laurent A1 McGreal, Steven R. A1 Apte, Udayan A1 Barry, Simon T. A1 Iredale, John P. A1 Clarke, Alan R. A1 Serrano, Manuel A1 Roskams, Tania A. A1 Sansom, Owen J. A1 Forbes, Stuart J. YR 2018 UL http://stm.sciencemag.org/content/10/454/eaan1230.abstract AB The liver is an excellent model of organ regeneration; however, regeneration may fail in a normal liver after acute severe injury such as acetaminophen poisoning. Bird and colleagues now show that a process that prevents proliferation termed senescence, which is classically associated with aging and carcinogenesis, inhibits the liver’s regenerative cells after acute injury. This senescence can be spread from cell to cell by the signaling molecule transforming growth factor–β (TGFβ). When TGFβ signaling was blocked during acetaminophen poisoning in mice, senescence was impeded, regeneration accelerated, and mouse survival increased. Therefore, targeting senescence induced by acute tissue injury is an attractive therapeutic approach to improve regeneration.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.