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)

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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:Nixon, Mr Colin and Clark, Mr William and Campbell, Mr Andrew and Kiourtis, Christos and Bryce, Mr Steven and Nibbs, Professor Rob and Clarke, Dr Mairi and Ridgway, Dr Rachel and Bird, Dr Thomas and Vincent, Mr David and Sansom, Professor Owen and Jamieson, Mr Thomas
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 > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
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

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