Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Research output: Contribution to journalArticlepeer-review

Authors

  • Sofia Ferreira-Gonzalez
  • 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

Colleges, School and Institutes

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.

Details

Original languageEnglish
Article number1020
Number of pages15
JournalNature Communications
Volume9
Issue number1
Early online date9 Mar 2018
Publication statusPublished - Dec 2018

Keywords

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