2026-05-22T02:42:41Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/188622024-11-29T19:42:52Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Bird, Thomas G author Müller, Miryam author Boulter, Luke author Vincent, David F author Ridgway, Rachel A author Lopez-Guadamillas, Elena author Lu, Wei-Yu author Jamieson, Thomas author Govaere, Olivier author Campbell, Andrew D author Ferreira-Gonzalez, Sofía author Cole, Alicia M author Hay, Trevor author Simpson, Kenneth J author Clark, William author Hedley, Ann author Clarke, Mairi author Gentaz, Pauline author Nixon, Colin author Bryce, Steven author Kiourtis, Christos author Sprangers, Joep author Nibbs, Robert J B author Van Rooijen, Nico author Bartholin, Laurent author McGreal, Steven R author Apte, Udayan author Barry, Simon T author Iredale, John P author Clarke, Alan R author Serrano, Manuel author Roskams, Tania A author Sansom, Owen J author Forbes, Stuart J author 2018-08-15 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. Sci Transl Med. 2018;10(454):eaan1230. 10.1126/scitranslmed.aan1230 1946-6242 Science translational medicine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420144/ 30111642 http://hdl.handle.net/20.500.12105/18862 TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.