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

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 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 TGFβ1 ligand. In acetaminophen poisoning inhibition of TGFβ receptor 1 (TGFβR1) improved survival. TGFβR1 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE111828 | GEO | 2019/03/20

REPOSITORIES: GEO

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Project description:We previously showed that severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in the hepatic response to injury remains a contentious topic. We have now used genetic lineage tracing of Hnf1Î²-expressing biliary duct cells to assess their contribution to LPC expansion and hepatocyte generation during normal liver homeostasis, and following different types of liver injury. We found that ductular reaction cells in human cirrhotic livers express HNF1Î². However, HNF1Î² expression was not present in newly generated EpCAM-positive hepatocytes. Using a tamoxifen-inducible Hnf1Î²CreER/R26RYFP/LacZ mouse, we show that there is no contribution of the biliary epithelium to hepatocyte turnover during liver homeostasis in healthy mice. Moreover, after loss of liver mass, Hnf1Î²+ LPC did not contribute to hepatocyte regeneration. We also assessed the contribution of Hnf1Î²+ cells following acute and repeated liver injury. All animal models showed expansion of LPC, as assessed by immunostaining and gene expression profile of sorted YFP-positive cells. A contribution of Hnf1Î²+ LPC to hepatocyte generation was not detected in animal models of liver injury with preserved hepatocyte regenerative potential such as acute acetaminophen, carbon tetrachloride injury, or chronic diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet. However, in mice fed with choline-deficient ethionine-supplemented (CDE)-diet, which causes profound hepatocyte damage and arrest, a small number of hepatocytes were derived from Hnf1Î²+ cells. Conclusion: Hnf1Î²+ cells do not participate in hepatocyte turnover in the healthy liver or during liver regeneration after partial hepatectomy. After liver injury, LPC arise from the biliary duct epithelium, which gives rise to a limited number of hepatocytes only when hepatocyte regeneration is compromised. Transcriptomic profile using MoGeneST-2.0 chip from 3 samples of YFP+ CDE, 3 samples of YFP+ DDC, 2 samples of YFP+ UTR and 3 samples YFP-

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

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