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Lookup NU author(s): Lucy Gee, Amy Collins, Lee Reed, Dr Lee Borthwick, Dr Christopher Morris, Dr Fiona LeBeauORCiD, Professor Fiona OakleyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): Kiourtis C, Terradas-Terradas M, Gee LM, May S, Georgakopoulou A, Collins AL, O'Sullivan ED, Baird DP, Hassan M, Shaw R, Tan EH, Muller M, Engelmann C, Andreola F, Hsieh Y-C, Reed LH, Borthwick LA, Nixon C, Clark W, Hanson PS, Sumpton D, Mackay G, Suzuki T, Najumudeen AK, Inman GJ, Campbell A, Barry ST, Quaglia A, Morris CM, LeBeau FEN, Sansom OJ, Kirschner K, Jalan R, Oakley F, Bird TG
Publication type: Article
Publication status: Published
Journal: Nature Cell Biology
Year: 2024
Pages: epub ahead of print
Online publication date: 13/11/2024
Acceptance date: 20/09/2024
Date deposited: 26/11/2024
ISSN (print): 1465-7392
ISSN (electronic): 1476-4679
Publisher: Nature Research
URL: https://doi.org/10.1038/s41556-024-01543-3
DOI: 10.1038/s41556-024-01543-3
Data Access Statement: Source metabolomics data can be found in Supplementary Table 6. The fastq files and processed data for the scRNA-seq analysis of mouse kidney cells and bulk tissue transcriptomics in liver and kidney can be found on the Gene Expression Omnibus repository (accession numbers GSE189726, GSE267196 and GSE262705). Source data are provided with this paper. All other data generated and/or analysed during the current study are available from the corresponding author on reason able request. No custom code or mathematical algorithms were used in this manuscript.
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