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Sci Transl Med. 2018 Aug 15;10(454). pii: eaan1230. doi: 10.1126/scitranslmed.aan1230.

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

Author information

1
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. t.bird@beatson.gla.ac.uk.
2
Medical Research Council (MRC) Centre for Regenerative Medicine, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
3
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH164TJ, UK.
4
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
5
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
6
Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
7
Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, B-3000 Leuven, Belgium.
8
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
9
Institute for Infection Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
10
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
11
Vrije Universiteit Medical Center, Department of Molecular Cell Biology, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands.
12
Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052, CNRS 5286, Lyon I University UMR S 1052, 69373 Lyon Cedex 08, France.
13
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
14
Oncology, IMED Biotech Unit, AstraZeneca, Cambridge CB2 0AA, UK.
15
University of Bristol, Senate House, Tyndall Avenue, Bristol BS8 1TH, UK.
16
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. t.bird@beatson.gla.ac.uk.
17
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, and Catalan Institution for Research and Advanced Studies, Barcelona, Spain.

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.

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