BACKGROUND: Disorders of the biliary tree develop and progress differently according to patient age. It is currently not known whether the ageing process affects the response to injury of cholangiocytes.
AIMS: The aim of the study was to identify molecular pathways associated to cholangiocyte ageing and to determine their effects in the biological response to injury of biliary cells.
METHODS: A panel of microRNAs (miRs) involved in ageing processes was evaluated in cholangiocytes of young and old mice (2 and 22 months of age respectively), subjected to a model of sclerosing cholangitis. Intracellular pathways common to elevated miRs were identified by in silico analysis. Cell proliferation and senescence were evaluated in Twinfilin-1 (Twf1) knocked-down cells. In vivo, senescence-accelerated prone mice (Samp8, a model for accelerated ageing), Twf1-\- or their respective controls were subjected to DDC.
RESULTS: Cholangiocytes from DDC-treated mice showed up-regulation of a panel of ageing-related miRs. Twf1 was identified by in silico analysis as a common target of the up-regulated miRs. Twf1 expression was increased both in aged and diseases cholangiocytes, and in human cholangiopathies. Knock-down of Twf1 in cholangiocytes reduced cell proliferation. Senescence and SASP markers expression increased in Twf1 knocked-down cholangiocytes upon pro-proliferative and pro-senescent (10 days LPS) stimulation. In vivo, Samp8 mice showed increased biliary proliferation,fibrosis and Twf1 protein expression level, while Twf1-/- had a tendency to lower biliary proliferation and fibrosis upon DDC administration compared to control animals.
CONCLUSION: We identified Twf1 as an important mediator of both cholangiocyte adaptation to ageing processes and response to injury. Our data suggest that disease and ageing might share common intracellular pathways. This article is protected by copyright. All rights reserved.