PLX194284

GSE111828: Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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 underlies 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 model a transcriptional signature associated with the induction of paracrine senescence is observed within twenty four hours, and is followed by one of impaired proliferation. In genetic models of hepatocyte injury and senescence we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended upon macrophage derived TGF1 ligand. In acetaminophen poisoning inhibition of TGF receptor 1 (TGFR1) improved survival. TGFR1 inhibition reduced senescence and enhanced liver regeneration even when delivered after the current therapeutic window. This mechanism, in which injury induced senescence impairs regeneration, is an attractive therapeutic target for acute liver failure. SOURCE: Thomas,Graham,Bird (t.bird@beatson.gla.ac.uk) - University of Edinburgh