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

TitleTGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.
Publication TypeJournal Article
Year of Publication2018
AuthorsBird TG, Müller M, Boulter L, Vincent DF, Ridgway RA, Lopez-Guadamillas E, Lu W-Y, Jamieson T, Govaere O, Campbell AD, Ferreira-González 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
JournalSci Transl Med
Volume10
Issue454
Date Published2018 Aug 15
ISSN1946-6242
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.

DOI10.1126/scitranslmed.aan1230
Alternate JournalSci Transl Med
PubMed ID30111642
Grant ListG0900992 / / Medical Research Council / United Kingdom
G1000868 / / Medical Research Council / United Kingdom
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