2026-08-30T08:30:45Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/188622024-11-29T19:42:52Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
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
funder
Wellcome Trust
funder
UK Research and Innovation
funder
United States Department of Health and Human Services
funder
Medical Research Council UK (MRC)
2024-02-28T11:16:19Z
2024-02-28T11:16:19Z
2018-08-15
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
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.
eng
TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.
journal article
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