Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

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Publication Details

Journal
Nature Cell Biology
Published
2024-11-13
DOI
https://doi.org/10.1038/s41556-024-01543-3
Citations
49
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
16.00

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article

Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ

Robin Shaw, Stephanie May, David Sumpton, Christos Kiourtis et al.
49 citations
Nature Cell Biology
Telomeres, Telomerase, and Senescence
16.00
article

Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ

Robin Shaw, Stephanie May, David Sumpton, Christos Kiourtis, Fiona Oakley, Maria Terradas-Terradas, William Clark, Gareth J. Inman, Mohsin Hassan, David Baird, Miryam Müller, Lee A. Borthwick, Fausto Andreola, Lee H. Reed, Peter S. Hanson, Toshiyasu Suzuki, Simon T. Barry, Ee Hong Tan, Thomas G. Bird, Rajiv Jalan, Colin Nixon, Αναστασία Γεωργακοπούλου, Kristina Kirschner, Fiona E. N. LeBeau, Andrew D. Campbell, Owen J. Sansom, Arafath K. Najumudeen, Lucy Gee, Gillian Mackay, Christopher M. Morris, Eoin O’Sullivan, Ya-Ching Hsieh, Amy Collins, Alberto Quaglia, Cornelius Engelmann
article en
49 citations

Abstract

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

Nature Cell BiologyVol. 26(12)
AstraZeneca (United Kingdom) (GB), Royal Free London NHS Foundation Trust (GB), Royal Brisbane and Women's Hospital (AU), Cancer Research UK (GB), European Foundation for the Study of Chronic Liver Failure (ES), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), CRUK Lung Cancer Centre of Excellence (GB), Centre for Inflammation Research (GB), The Queen's Medical Research Institute (GB), University College London (GB), Charité - Universitätsmedizin Berlin (DE), University of Glasgow (GB), Newcastle University (GB), University of Edinburgh (GB)
Wellcome, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, Rosetrees Trust, Horizon 2020 Framework Programme, Medical Research Council, Medical Research Foundation
Good health and well-being
Openalex Percentile: Top 1%
Telomeres, Telomerase, and Senescence
16.00
DOIOpen Access PDFOpenAlex
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