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, Stuart J. Forbes

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number1020
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 9 Mar 2018

Keywords

  • Bile ducts
  • Liver fibrosis
  • Mechanisms of disease
  • Senescence

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