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

Bird, T. G. et al. (2018) TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Science Translational Medicine, 10(454), eaan1230. (doi: 10.1126/scitranslmed.aan1230) (PMID:30111642) (PMCID:PMC6420144)

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.

• Item Type: Articles
• Additional Information: T.G.B. was funded by the Wellcome Trust (WT081604AIA and WT107492Z). S.J.F. was funded by a Medical Research Council (MRC) project grant (G1000868), the Wellcome Trust, the Sir Jules Thorn Charitable Trust, and Scottish Enterprise. J.P.I. was supported by an MRC program grant. O.J.S. was supported by CRUK grant # A12481. U.A. was supported by NIH grant # R01 DK98414.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Clark, Mr William and Bryce, Mr Steven and Nibbs, Professor Rob and Clarke, Dr Mairi and Vincent, Mr David and Bird, Dr Thomas and Jamieson, Mr Thomas and Nixon, Mr Colin and Kiourtis, Christos and Ridgway, Dr Rachel and Sansom, Professor Owen and Campbell, Dr Andrew
• Authors: Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., Ferreira Gonzalez, S., Cole, A. M., Hay, T., Simpson, K. J., Clark, W., Hedley, A., Clarke, M., Gentaz, P., Nixon, C., Bryce, S., Kiourtis, C., Sprangers, J., Nibbs, R. J.B., Van Rooijen, N., Bartholin, L., McGreal, S. R., Apte, U., Barry, S. T., Iredale, J. P., Clarke, A. R., Serrano, M., Roskams, T. A., Sansom, O. J., and Forbes, S. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Science Translational Medicine
• Publisher: American Association for the Advancement of Science
• ISSN: 1946-6234
• ISSN (Online): 1946-6242
• Copyright Holders: Copyright © 2019 American Association for the Advancement of Science
• First Published: First published in Science Translational Medicine 10(454):eaan1230
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher