Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Sofia Ferreira-Gonzalez, Wei-Yu Lu, Alexander Raven, Benjamin Dwyer, Tak Yung Man, Eoghan O’Duibhir, Philip J. Starkey Lewis, Lara Campana, Tim J. Kendall, Thomas G. Bird, Nuria Tarrats, Juan-Carlos Acosta, Luke Boulter and Stuart J. Forbes ()
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Sofia Ferreira-Gonzalez: University of Edinburgh
Wei-Yu Lu: University of Edinburgh
Alexander Raven: University of Edinburgh
Benjamin Dwyer: University of Edinburgh
Tak Yung Man: University of Edinburgh
Eoghan O’Duibhir: University of Edinburgh
Philip J. Starkey Lewis: University of Edinburgh
Lara Campana: University of Edinburgh
Tim J. Kendall: University of Edinburgh
Thomas G. Bird: University of Edinburgh
Nuria Tarrats: University of Edinburgh
Juan-Carlos Acosta: University of Edinburgh
Luke Boulter: University of Edinburgh
Stuart J. Forbes: University of Edinburgh

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.

Date: 2018
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DOI: 10.1038/s41467-018-03299-5

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